Benzimidazole derivatives

ABSTRACT

This invention provides compounds having the structure:                    
     wherein each of R 1 , R 2 , R 3  and R 9  is independently H; straight chain or branched, substituted or unsubstituted C 1 -C 7  alkyl, C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; acyl, phenyl, substituted phenyl, or heteroaryl; wherein each dashed line represents a single bond or a double bond with the proviso that if R 1  is present, R 3  is absent and there is a double bond between N at position 3 and C at position 2 and a single bond between C at position 2 and N at position 1 and if R 3  is present, R 1  is absent and there is a double bond between N at position 1 and C at position 2 and a single bond between C at position 2 and N at position 3; wherein each of R 4 , R 5  and R 6  is independently H, F, Cl, Br, I; straight chain or branched, substituted or unsubstituted C 1 -C 7  alkyl, C 2 -C 7  alkenyl or alkynyl; C 3 -C 7  cycloalkyl or cycloalkenyl; phenyl, substituted phenyl, heteroaryl, —OH, —OR 7 , —CN, —COR 7 , —CO 2 R 7 , —CON(R 7 ) 2 , —OCOR 7 , —SR 7 , —N(R 7 ) 2 , —NR 7 COR 7 , —(CH 2 ) n OR 7 , —(CH 2 ) n N(R 7 ) 2 , —(CH 2 ) n NR 7 COR 7 , wherein n is an integer from 1 to 4; and wherein each of R 7  and R 8  is independently H; straight chain or branched, substituted or unsubstituted C 1 -C 7  alkyl, C 2 -C 7  alkenyl or alkynyl; phenyl or substituted phenyl. 
     These compounds are selective for cloned human alpha 2 receptors and are useful as analgesic, sedative or anaesthetic agents.

This application is a divisional of U.S. Ser. No. 09/232,490, filed Jan.15, 1999, U.S. Pat. No. 6,316,637, which is a continuation of U.S. Ser.No. 08/765,656, filed Mar. 25, 1997, now abandoned, which was a §371national stage application of PCT International Application No.PCT/US95/09895, filed Aug. 4, 1995 on behalf of Synaptic PharmaceuticalCorporation, claiming priority of and a continuation-in-part of U.S.Ser. No. 08/285,956, filed Aug. 4, 1994, now abandoned, the contents ofall of which are hereby incorporated by reference into this application.Throughout this application, various references are referred to withinparenthesis. Disclosure of these publications in their entireties arehereby incorporated by reference into this application to more fullydescribe the state of the art to which this invention pertains.

BACKGROUND OF THE INVENTION

Alpha adrenergic receptors are plasma membrane receptors which arelocated in the peripheral and central nervous systems throughout thebody. They are members of a diverse family of structurally relatedreceptors which contain seven putative helical domains and transducesignals by coupling to guanine nucleotide binding proteins (G-proteins).These receptors are important for controlling many physiologicalfunctions and, thus, have been important targets for drug developmentduring the past 40 years. Examples of alpha adrenergic drugs includeclonidine, phenoxybenzamine and prazosin (for treatment ofhypertension), naphazoline (for nasal decongestion), medetomidine (forveterinary analgesia), UK-14,304 and p-aminoclonidine (for glaucoma).However, most of these drugs produce undesirable side effects which maybe due to the their interactions with other receptor subtypes. Forexample, clonidine is a well known centrally acting antihypertensiveagent. However, it also produces untoward side effects such asanalgesia, sedation, bradycardia and dry mouth which may be due to itslack of selectivity for a specific receptor subtype, i.e. α₂ receptor.

Alpha adrenoceptors were originally proposed to have only two(alpha andbeta) subtypes (Berthelsen, S.; Pethinger W. Life Sci. 1977, 21, 595).However, modern molecular biological and pharmacological techniques haveled to the identification of at least 6 subtypes (α_(1a), α_(1b),α_(2a), α_(2b) and α_(2c)) of the adrenoceptors (Bylund, D. B., TrendsPharmacol. Sci. 1988, 9, 356; Weinshank et al, U.S. Pat. No. 5,053,337,issued Oct. 1, 1991; Bard et al, International Publication No. WO94/08040, published Apr. 14, 1994).

Among many other therapeutic indications, α₂ receptors are believed tomodulate pain and behavioral depression by regulating locus coeruleusfiring. In addition, α₂ receptors are well known to be involved ineffects on blood pressure, heart rate, vasoconstriction and glaucoma.However, it is not known which therapeutic. indications are controlledby each of these subtypes.

The effects of alpha-2 receptor agonists on analgesia, anesthesia andsedation have been well documented for past 10 years (Pertovaara, A.,Progress in Neurobiology, 1993, 40, 691). For example, systematicadministration of clonidine has been shown to produce antinociception invarious species including human patients in addition to its well knownsedative effects. Intrathecal and epidural administration of clonidinehas also proved effective in producing antinociception. Another alpha-2agonist, Medetomidine, which has better alpha-2/alpha-1 selectivity andis more potent at alpha-2 receptors than clonidine, has been extensivelystudied for its antinociception effect. In the spinally-initiatedheat-induced tail flick test in rats, systematic administration ofmedetomidine produced a dose-dependent antinociception which could betotally reversed by alpha-2 receptor antagonists, atipamazole oridazoxan. Experimental studies of medetomidine on pain sensitivity inhumans also indicated that this agent is very effective on ischemicpains, even though effective drug doses were high enough to produce asedation and considerable decrease in blood pressure.

Effects of alpha-2 receptor agonists in anaesthetic practice have alsobeen investigated. The sedative effect of alpha-2 agonists is regardedas good component of premedication. Another beneficial effect of alpha-2agonists in anaesthetic practice is their ability to potentiate theanaesthetic action of other agents and to reduce anaestheticrequirements of other drugs during surgery. Studies shows thatpremedication with 5 μg k⁻¹ of oral clonidine administration reducedfentanyl requirements for induction and intubation by 45% in patientundergoing aortocoronary bypass surgery (Ghingnone, M, et al,Anesthesiology 1986, 64, 36).

This invention is directed to novel benzimidazole derivatives which areselective for cloned human alpha 2 receptors. This invention is alsorelated to uses of these compounds as analgesic, sedative andanaesthetic agents. In addition, this invention includes using suchcompounds for lowering intraocular pressure, and treatment of migraine,hypertension, alcohol withdrawal, drug addiction, rheumatoid arthritis,ischemia, spasticity, diarrhea, nasal decongestion. Furthermore thecompounds may be useful as cognition enhancers.

SUMMARY OF THE INVENTION

This invention provides compounds having the structure:

wherein each of R₁, R₂, R₃ and R₉ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; acyl, phenyl, substitutedphenyl, or heteroaryl; wherein each dashed line represents a single bondor a double bond with the proviso that if R₁ is. present, R₃ is absentand there is a double bond between N at position 3 and C at position 2and a single bond between C at position 2 and N at position 1 and if R₃is present, R₁ is absent and there is a double bond between N atposition 1 and C at position 2 and a single bond between C at position 2and N at position 3; wherein each of R₄, R₅ and R₆ is independently H,F, Cl, Br, I; straight chain or branched, substituted or unsubstitutedC₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl;phenyl, substituted phenyl, heteroaryl, —OH, —OR₇, —CN, —COR₇, —CO₂R₇,—CON (R₇)₂, —OCOR₇, —SR₇, —N (R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇, —(CH₂)_(n)N (R₇)₂, —(CH₂)_(n)NR₇COR₇, wherein n is an integer from 1 to 4;and wherein each of R₇ and R₈ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; phenyl or substituted phenyl.

These compounds are selective for cloned human alpha 2 receptors and areuseful as analgesic, sedative or anaesthetic agents.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds having the structure:

where each of R₁, R₂, R₃ and R₉ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; acyl, phenyl, substitutedphenyl, or heteroaryl; where each dashed line represents a single bondor a double bond with the proviso that if R₁ is present, R₃ is absentand there is a double bond between N at position 3 and C at position 2and a single bond between C at position 2 and N at position 1 and if R₃is present, R₁ is absent and there is a double bond between N atposition 1 and C at position 2 and a single bond between C at position 2and N at position 3; where each of R₄, R₅ and R₆ is independently H, F,Cl, Br, I; straight chain or branched, substituted or unsubstitutedC₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl;phenyl, substituted phenyl, heteroaryl, —OH, —OR₇, —CN, —COR₇, —CO₂R₇,—CON(R₇)₂, —OCOR₇, —SR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇,—(CH₂)_(n)N(R₇)₂, —(CH₂)_(n)NR₇COR₇, where n is an integer from 1 to 4;and where each of R₇ and R₈ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; phenyl or substituted phenyl.

The compound may have the following preferred structure:

where each of R₁, R₂, R₃, R₄ and R₆ is defined above.

In addition, the invention further describes compounds having thefollowing structures:

Acid salts of the compounds described above may be also be prepared. Theacid salts may be but are not limited to the following HCl, HBr, HI,H₂SO₄, CH₃COOH, CF₃COOH, HNO₃, CF₃SO₃H, CH₃SO₃H, C₄H₄O₄, HO₂CCH═CHCO₂H,HO₂CCH═CHCO₂H, HO₂CCH (OH) CH (OH) CO₂H.

The invention also describes a pharmaceutical composition comprising atherapeutically effective amount of the compounds described above and apharmaceutically acceptable carrier.

The invention further describes a method for treating an alpha-2adrenergic receptor associated disorder or alleviating pain in a subjectwhich comprises administering to the subject an amount of a compoundhaving the structure:

where each of R₁, R₂, R₃, R₄, R₅, R₆, R₇, R₈ and R₉ is defined above.

The invention describes a method for treating an alpha-2 adrenergicreceptor associated disorder or alleviating pain in a subject whichcomprises administering to the subject an amount of a compound havingthe structure:

where each of R₁, R₂, R₃, R₄ and R₆ is defined above.

The invention describes a method for alleviating pain in a subject whichcomprises administering to the subject an amount of a compound havingthe structure:

The method described above may be used to treat alpha-2 adrenergicreceptor associated disorders such as hypertension, rheumatoidarthritis, ischemia, spasticity, glaucoma, migraines, alcoholwithdrawal, drug addiction, diarrhea, or nasal congestion.

The compounds may be administered to a subject suffering from an alpha-2adrenergic receptor associated disorder. The effective quantity of thecompounds described above is from about 0.01 mg/dose to about 100mg/dose and preferably from about 0.1 mg/dose to about 20 mg/dose. Suchdose levels will depend upon the half-life of the compounds see forexample Goodman and Gilman's “The Pharmacological Basis ofTherapeutics,” Eighth Edition, 1990, Pergamon Press, pages 3-32.

Administration for the above compounds may be by any conventional routeof administration, including, but not limited to, intravenous,intramuscular, oral, ophthalmic, subcutaneous, intratumoral,intradermal, and parenteral.

The present invention also provides compounds useful for preparing apharmaceutical composition comprising any of the compounds disclosedherein and a pharmaceutically acceptable carrier. The composition maycontain between 0.1 mg and 500 mg of any of the compounds, and may beconstituted in any form suitable for the mode of administrationselected.

The compounds may be administered neat or with a pharmaceutical carrierto a patient in need thereof. The pharmaceutical carrier may be solid orliquid.

A solid carrier can include one or more substances which may also act asflavoring agents, lubricants, solubilizers, suspending agents, fillers,glidants, compression aids, binders or tablet-disintegrating agents; itcan also be an encapsulating material. In powders, the carrier is afinely divided solid which is in admixture with the finely dividedactive ingredient. In tablets, the active ingredient is mixed with acarrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired.

The powders and tablets preferably contain up to 99% of the activeingredient. Suitable solid carriers include, for example, calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, polyvinylpyrrolidine, low melting waxes and ionexchange resins.

Liquid carriers are used in preparing solutions, suspensions, emulsions,syrups, elixirs and pressurized compositions. The active ingredient canbe dissolved or suspended in a pharmaceutically acceptable liquidcarrier such as water, an organic solvent, a mixture of both orpharmaceutically acceptable oils or fats. The liquid carrier can containother suitable pharmaceutical is additives such as solubilizers,emulsifiers, buffers, preservatives, sweeteners, flavoring agents,suspending agents, thickening agents, colors, viscosity regulators,stabilizers or osmo-regulators. Suitable examples of liquid carriers fororal and parenteral administration include water (partially containingadditives as above, e.g. cellulose derivatives, preferably sodiumcarboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g. glycols) and their derivatives,and oils (e.g. fractionated coconut oil and arachis oil). For parenteraladministration, the carrier can also be an oily ester such as ethyloleate and isopropyl myristate. Sterile liquid carriers are useful insterile liquid form compositions for parenteral administration. Theliquid carrier for pressurized compositions can be halogenatedhydrocarbon or other pharmaceutically acceptable propellent.

Liquid pharmaceutical compositions which are sterile solutions orsuspensions can be utilized by for example, intramuscular,intraperitoneal or subcutaneous injection.

Sterile solutions can also be administered intravenously.

The compounds may be prepared as a sterile solid composition which maybe dissolved or suspended at the time of administration using sterilewater, saline, or other appropriate sterile injectable medium. Carriersare intended to include necessary and inert binders, suspending agents,lubricants, flavorants, sweeteners, preservatives, dyes, and coatings.

The compound can be administered orally in the form of a sterilesolution or suspension containing other solutes or suspending agents,for example, enough saline or glucose to make the solution isotonic,bile salts, acacia, gelatin, sorbitan monoleate, polysorbate 80 (oleateesters of sorbitol and its anhydrides copolymerized with ethylene oxide)and the like.

The compound can also be administered orally either in liquid or solidcomposition form. Compositions suitable for oral administration, includesolid forms, such as pills, capsules, granules, tablets, and powders,and liquid forms, such as solutions, syrups, elixirs, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions, and suspensions.

Optimal dosages to be administered may be determined by those skilled inthe art, and will vary with the particular compound in use, the strengthof the preparation, the mode of administration, and the advancement ofthe disease condition. Additional factors depending on the particularsubject being treated will result in a need to adjust dosages, includingsubject age, weight, gender, diet, and time of administration.

This invention will be better understood from the Experimental Detailswhich follow. However, one skilled in the art will readily appreciatethat the specific methods and results discussed are merely illustrativeof the invention as described more fully in the claims which followthereafter.

EXPERIMENTAL DETAILS General Methods

Four general synthetic methods were used to synthesize the compoundsdescribed herein. These methods are illustrated in Reaction Schemes 1-4.

The compounds herein have been prepared using synthetic sequences shownin Schemes 1-4. C-4 halogen substituted 5-aminobenzimidazoles wereobtained from commercially available 5-nitrobenzimidazole by thesequence of hydrogenation and halogenation. C-4 alkyl substitutedanalogs were prepared in a similar reaction sequence in which alkylgroup was incorporated using a Grignard reaction (Scheme 1). Reaction of5-aminobenzimidazole with 2-imidazoline-2-sulfonic acid (ISA) which wasobtained from 2-imidazolinethione (Gluchowski, C. U.S. Pat. No.5,130,441) provides access to 2-aminoimidazolines in high yield(45-95%). C-2 substituted 5-nitrobenzimidazoles were prepared bycondensation of 4-nitro-1,2-phenylenediamine with corresponding acids(Scheme 2). C-2 substituted 5-nitrobenzimidazoles were subjected to thesame reaction sequence as Scheme 1 to provide the desired final product.Reaction of alkyl halides with 5-nitrobenzimidazole in the presence ofNaH provided both N-1 and N-3 substituted benzimidazoles (Scheme 3). Thereaction mixtures were subjected to hydrogenation (H₂/Pd-C) to producethe corresponding amines, which were separated on column chromatography.Each amine was subjected to the reaction sequence described in Scheme 1to provide the final product.

Preparation of C-7 substituted benzimidazoles is illustrated in Scheme4. Halogenation of 2,4-dinitroaniline provided 6-halogen substitutedanilines, which were subjected to hydrogenation and condensation informic acid to provide 7-halosubstituted 5-aminobenzimidazoles. Theseintermediates were coupled to ISA to provide the desired products. C-7alkyl substituted benzimidazoles were prepared using a similar sequenceof reactions. Accordingly, 6-bromo-2,4-dinitroaniline was converted to6-alkyl or aryl substituted analogs by the Pd(II) catalyzed couplingreaction. Conversion of alkyl substituted anilines to benzimidazoles wascarried out in same reaction sequences described in Scheme 2.

EXAMPLE 1 5-(2-Imidazolin-2-ylamino)Benzimidazole (#1)

5-Aminobenzimidazole.

A solution of 5-nitrobenzimidazole (4.0 g, 25 mmol) and 10% Pd/C (0.5 g)was stirred under H₂ for 12 h. The reaction mixture was filtered throughCelite-assisted funnel and concentrated in vacuo, yielding 3.2 g (25mmol, >95%) of the desired product, which was characterized by NMR andsubjected to following reactions without further purification.

2-Imidazoline-2-sulfonic Acid (ISA).

ISA was prepared according to the procedure described in literature(Gluchowski, C. U.S. Pat. No. 5,130,441, 1992). To a solution of2-imidazolinethione (6.6 g, 65 mmol), sodium molybdate(IV) dihydrate(0.5 g, 2.1 mmol) and NaCl (1.5 g) in 150 ml of distilled water wasadded 30% of H₂O₂ (50 ml, 450 mmol) for 1 h at −10° C. The reactionmixture was stored at −20° C. for 12 h and then reaction temperature wasslowly warmed up to 25° C. The white crystal obtained was filtered anddried in vacuo to provide 2.8 g (21 mmol, 32%) of the acid. The compoundwas used in the examples noted below.

5-(2-Imidazolin-2-ylamino)Benzimidazole.

A solution of 5-aminobenzimidazole (1.0 g, 7.5 mmol) and ISA (2.5 g,18.8 mmol) in 10 ml of isobutanol was stirred at reflux for 12 h. Thereaction mixture was concentrated in vacuo to yield an oily residuewhich was subjected to silica gel column chromatography (20% NH₃ sat'dMeOH/EtOAc) to produce 0.77 g (3.8 mmol, 53%) of the product. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom MeOH to afford 0.21 g (27%) of the product as a white solid: mp196-198° C.; Anal. Calc. for C₁₀H₁₁N₅.1.0C₄H₄O₄.1.3H₂O requires C,49.62; H, 4.65; N, 20.67. Found: C, 49.65; H, 5.73; N, 20.53.

EXAMPLE 2 4-Bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#2)

4-Bromo-5-aminobenzimidazole.

To a solution of 5-aminobenzimidazole (3.3 g, 2.3 mmol) in 30 ml of AcOHwas added bromine (0.055 ml, 1.1 mmol) in a portion and resultingreaction mixture was stirred for 0.5 h at 25° C. Reaction mixture wasconcentrated in vacuo, yielding a dark brown solid which was subjectedto silica gel column chromatography (NH₃ saturated 10% MeOH/EtOAc) toyield 0.22 g (0.97 mmol, 42%) of the desired product.

4-Bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of 4-bromo-5-aminobenzimidazole (0.22 g, 0.97 mmol) and ISA(0.34 g, 2.5 mmol) in 5 ml of isobutanol was stirred at reflux for 12 h.Reaction mixture was concentrated in vacuo and subjected to silica gelcolumn chromatography (NH₃ saturated 20% MeOH/EtOAc) to yield 0.23 g(0.83 mmol, 84%) of the product. The product obtained was converted tothe fumarate salt and recrystallized from MeOH to afford 0.12 g (30%) ofthe product as a white solid: mp 199-202° C.; Anal. Calc. forC₁₀H₁₀N₅Br.1.0C₄H₄O₄.0.7H₂O requires C, 41.13; H, 3.80; N, 17.13. Found:C, 41.60; H, 3.81; N, 16.97.

EXAMPLE 3 4-Chloro-5-(2-imidazolin-2-ylamino)Benzimidazole (#3)

4-Chloro-5-aminobenzimidazole.

To a solution of 5-aminobenzimidazole (1.0 g, 7.5 mmol) in 20 ml of AcOHwas added Cl₂ saturated AcOH solution until it produced a precipitation.The reaction mixture was concentrated in vacuo, yielding a dark residuewhich was subjected to column chromatography (NH₃ sat'd 30% MeOH/EtOAc)to yield 120 mg (0.72 mmol) of 4-chloro-5-aminobenzimidazole.

4-Chloro-5-(2-imidazolin-2-ylamino)Benzimidazole.

The amine (120 mg, 0.72 mmol) was mixed with ISA (250 mg, 1.8 mmol), andresulting mixture was stirred for 12 h at reflux. Column chromatographicseparation (NH₃ sat'd 30% MeOH/EtOAc) of the reaction mixture yielded140 mg (0.62 mmol, 87%) of the desired product. The product obtained wasconverted to the fumarate salt and recrystallized from EtOH to afford 50mg (20%) of the product as a white solid: mp 207-208° C.; Anal. Calc.for C₁₀H₁₀N₅Cl.1.0C₄H₄O₄.0.6H₂O requires C, 46.38; H 4.23; N, 19.32.Found: C. 46.32; H, 4.23; N, 19.47.

EXAMPLE 4 4-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#4)

4-Methyl-5-aminobenzimidazole.

A solution of 4-bromo-5-aminobenzimidazole (180 mg, 0.84 mmol),tetramethyltin (330 mg, 2.4 mmol) and bis(triphenylphosphine)palladium(II) chloride (20 mg) in 5 ml of anhydrous DMF was placed in sealed tubeand stirred for 12 h at 145° C. The reaction mixture was concentrated invacuo, yielding an oily residue which was subjected to columnchromatographic separation (NH₃ sat'd 10% MeOH/EtOAc) to yield 140 mg(0.83 mmol, >95%) of 4-methyl-5-aminobenzimidazole.

4-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

The amine obtained was placed in flask with ISA (0.38 g, 2.5 mmol) and 5ml of isobutanol, and resulting mixture was stirred at reflux for 12 h.Column chromatographic separation (NH₃ sat,d 10 MeOH/EtOAc) of thereaction mixture provided 0.15 g (0.71 mmol, 84%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 92 mg (25%) of the product as a whitesolid: mp 155-157° C.; Anal. Calc. for C₁₀H₁₃N₅.1.5C₄H₄.0.5H₂O requiresC, 52.08; H, 4.96; N, 17.86. Found: C, 52.08; H, 4.97; N, 17.80.

EXAMPLE 5 4-Iodo-5-(2-imidazolin-2-ylamino)Benzimidazole (#5)

4-lodo-5-aminobenzimidazole.

To a solution of 5-aminobenzimidazole (0.6 g, 4.5 mmol) and Hg(OAc)₂(1.72 g, 5.5 mmol) in 20 ml of AcOH was added a solution of I₂ untilsolution produces a precipitation. The reaction mixture was concentratedin vacuo, yielding an oily residue which was subjected to columnchromatographic separation (NH₃ sat'd 10% MeOH/EtOAc) to produce 0.30(1.2 mmol, 26%) g of 4-iodo-5-aminobenzimidazole.

4-Iodo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of the amine (0.30 g, 1.1 mmol) and ISA (0.62 g, 4.4 mmol)was stirred at reflux for 12 h. Column chromatographic separation of thereaction mixture (NH₃ sat'd 20% MeOH/EtOAc) provided 0.12 g (0.34 mmol,31%) of the desired product. The product obtained was converted to thefumarate salt and recrystallized from EtOH to afford 0.12 g (20%) of theproduct as a white solid:.mp 256° C.; Anal. Calc. forC₁₀H₁₀N₅I.2.0C₄H₄.1.0H₂O requires C, 37.45; H, 3.49; N, 12.13. Found: C,37.52; H, 3.51; N, 12.62.

EXAMPLE 6 4-Ethyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#6)

4-Ethyl-5-aminobenzimidazole.

To a solution of 5-nitro-benzimidazole (2.8 g, 17 mmol) in THF was added16 ml of EtMgBr solution (48 mmol) and reaction mixture was stirred for2 h at −15° C. A solution of tetrachloro-1,4-benzoquinone (8.8 g, 36mmol) in THF was added dropwise into reaction mixture, which was allowedto warm up to 25° C. over 1 h. Silica gel(20 g) was added into reactionmixture and solvent was removed in vacuo to provide a brown silica gelpowder which was subjected to column chromatography (EtOAc, neat) toprovide 1.7 g (8.9 mmol, 52%) of 4-ethyl-5-nitrobenzimidazole, which wassubsequently subjected to hydrogenation (H₂, Pd/C) to yield 1.32 g (8.2mmol) of 4-ethyl-5-aminobenzimidazole.

4-Ethyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of the amine (0.71 g, 4.3 mmol) and ISA (0.75 g, 5.6 mmol) in10 ml of isobutanol was stirred at reflux for 12 h. The reaction mixturewas concentrated in vacuo, yielding an oil, which was subjected tocolumn chromatography (NH₃ sat'd 30% EtOH/EtOAc) to yield 0.26 g (1.2mmol, 28%) of the desired product. The product obtained was converted tothe fumarate salt and recrystallized from MeOH to afford 0.22 g (16%) ofthe product as a light brown solid: mp 238-239° C.; Anal. Calc. forC₁₂H₁₅N₅.1.0C₄H₄O₄ requires C, 55.60; H, 5.55; N, 20.28. Found: C,54.63; H, 5.70; N, 19.46.

EXAMPLE 7 4-n-Propyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#7)

4-n-Propyl-5-aminobenzimidazole.

To a solution of 5-nitrobenzimidazole (2.3 g, 14 mmol) was added 14 mlof n-PrMgBr solution (42 mmol) and reaction mixture was stirred for 2 hat −15° C. The reaction was quenched by adding a solution oftetrachloro-1,4-benzoquinone (4 g, 16 mmol) in 10 ml of THF. Thereaction mixture was concentrated in vacuo to provide an oil, which wassubjected to column chromatographic separation (EtOAc, neat) to provide1.4 g (7.2 mmol, 52%) of 4-n-propyl-5-nitrobenzimidazole, which wasconverted to the corresponding amine (1.2 g, >95%) by hydrogenation(H₂,Pd/C).

4-n-Propyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

The amine (1.2 g, 14 mmol) was stirred with ISA (1.5 g, 11.2 mmol) atreflux for 12 h. Concentration of reaction mixture produced an oilyresidue, which was subjected to column chromatographic separation (NH₃sat'd 30% MeOH/EtOAc) to provide 0.63 g (2.6 mmol, 37%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from EtOH to afford 0.45 g (16%) of the product as alight brown solid: mp 229-230° C.

EXAMPLE 8 4-n-Butyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#8)

4-n-Butyl-5-aminobenzimidazole.

To a solution of 5-nitrobenzimidazole (0.41 g, 2.5 mmol) was added asolution of n-BuLi (7.5 mmol) and reaction mixture was stirred for 1 hat 0° C. The reaction mixture was quenched by adding a few drops of H₂Oand concentrated in vacuo yielding an oil which was subjected to silicagel column chromatography (5% MeOH/EtOAC) to provide 0.13 g of4-n-butyl-5-nitrobenzimidazole and 0.19 g of4-n-butyl-5-aminobenzimidazole. The nitrobenzimidazole was converted tothe amine in hydrogenation (H₂/Pd-C) to provide 0.28 g (1.5 mmol, 60%)of the desired product.

4-n-Butyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

The amine (0.28 g, 1.5 mmol) was refluxed with ISA (0.50 g, 3.7 mmol) inisobutanol for 12 h. Column chromatographic separation of reactionmixture (NH₃ sated 20% MeOH/EtOAc) provided 0.21 g (0.81 mmol, 54%) ofthe product. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.38 g (49%) of the product asa foamy solid: mp 96° C.; Anal. Calc. for C₁₄H₁₉N₅.2.0C₄H₄O₄. requiresC, 55.68; H, 5.86; N, 16.23. Found: C, 55.98; H, 5.68; N, 16.49.

EXAMPLE 9 1-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#9)

1- and 3-Methyl-5-aminobenzimidazole.

A solution of 5-nitrobenzimidazole (3.0 g, 18.4 mmol) in 100 ml of THFwas stirred with NaH (2.7 g, 36.8 mmol) for 0.5 h at 25° C. To thesolution was added methyl iodide (2.0 ml, 20.3 mmol) and resultingmixture was stirred for 12 h. The reaction mixture was concentrated invacuo to provide an oil, which was dissolved in 200 ml of MeOH andstirred with 0.3 g of 10% Pd/C under H₂ for 12 h. The reaction mixturewas filtered and concentrated in vacuo, yielding a dark oily residuewhich was subjected to column chromatography (3% MeOH/CHCl₃) to provide0.69 g (3.9 mmol, 21%) of 1-methyl-5-aminobenzimidazole and 0.36 g (2.0mmol, 11%) of 3-methyl-5-aminobenzimidazole.

1-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of 1-methyl-5-aminobenzimidazole (0.15 g, 1.1 mmol) and ISA(0.30 g, 2.2 mmol) in 3 ml of isobutanol was stirred at reflux for 12 h.The reaction mixture was concentrated in vacuo, yielding an oily residuewhich was purified on silica gel column chromatography (NH₃ sat'd 20%isopropanol/EtOAc) to yield 0.12 g (0.56 mmol, 51%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.11 g (30%) of the product asa white crystal: mp 210-211° C.; Anal. Calc. forC₁₁H₁₃N₅.1.0C₄H₄O_(4-0.3)H₂O requires C, 35.36; H. 5.28; N,20.74. Found:C, 53.67; H, 5.13; N, 20.70.

EXAMPLE 10 1-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#10)

1-Methyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-methyl-5-aminobenzimidazole (0.36 g, 2.4 mmol) in 10ml of AcOH was added Br₂ (0.12 ml). The reaction mixture was stirred for1 h at 25° C. and concentrated in vacuo, yielding an oil which wassubjected to column chromatography (NH₃ sat'd 3% MeOH/CHCl₃) to yield0.27 g (1.2 mmol, 50%) of the desired product.

1-Methyl1-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

Isobutanolic solution of the amine (0.27 g, 1.2 mmol) and ISA (0.6 g,4.5 mmol) was stirred at reflux for 12 h. The reaction mixture wasconcentrated in vacuo, yielding an oily residue which was subjected tocolumn chromatography (NH₃ sat'd 20% MeOH/EtOAc) to yield 0.33 9 (1.1mmol, 92%) of the expected product. The product obtained wasrecrystallized from EtOH to afford 0.21 g (64%) of the product as awhite crystal: mp 237-238° C.; Anal. Calc. for C₁₁H₁₂N₅Br.1.75H₂Orequires C, 40.57; H, 4.80; N, 21.50. Found: C, 40.98; H, 4.81; N,21.41.

EXAMPLE 11 3-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole. (#11)

A solution of 3-methyl-5-aminobenzimidazole (0.20 g, 1.5 mmol) and ISA(0.45 g, 3.4 mmol) was stirred at reflux for 12 h. The reaction mixturewas concentrated in vacuo and purified on column chromatography (NH₃sat'd 20% MeOH/EtOAc) to yield 0.19 g (0.88 mmol, 59%) of the product.The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 0.31 g (46%) of the product as awhite crystal: mp 202-204° C.; Anal. Calc. for C₁₁H₁₃N₅.2.0C₄H₄H₄requires C, 51.01; H, 4.73; N,15.65. Found: C, 51.65; H, 4.76; N, 15.78.

EXAMPLE 12 3-Methyl-4-bromo-5-(imidazolin-2-ylamino)Benzimidazole (#12)

3-Methyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-methyl-5-aminobenzimidazole (0.27 g, 1.8 mmol) in 10ml of AcOH was added Br₂ (0.10 ml). The reaction mixture was stirred for1 h at 25° C. and concentrated in vacuo, yielding an oil which wassubjected to column chromatography (NH₃ sat'd 3% MeOH/CHCl₃) to yield0.14 g (0.62 mmol, 356?) of the desired product.

3-Methyl-4-bromo-5-(imidazolin-2-ylamino)Benzimidazole.

A solution of 3-methyl-4-bromo-5-aminobenzimidazole (0.31 g, 1.4 mmol)and ISA (0.6 g, 4.5 mmol) in 10 ml of isobutanol was stirred at refluxfor 12 h. Oily residue obtained was subjected to column chromatography(NH₃ sat'd 20% isopropanol/EtOAc) to yield 0.39 g (1.3 mmol, 93%) of thedesired product. The product obtained was converted to the fumarate saltand recrystallized from MeOH to afford 0.50 g (68%) of the product as awhite solid: mp 209-210° C.; Anal. Calc. for C₁₁H₁₂N₅Br.2.0C₄H₄O₄.requires C, 43.36; H, 3.83; N, 13.31. Found: C, 43.66; H, 3.84; N,13.10.

EXAMPLE 13 1-Propyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#13)

1- and 3-Propyl-5-aminobenzimidazole.

A solution of 5-nitrobenzimidazole (3.6 g, 23 mmol) in 100 ml of THF wasstirred with NaH (1.5 g, 33 mmol) for 0.5 h at 25° C. To the solutionwas added allyl bromide (4.8 ml, 57 mmol) and resulting mixture wasstirred for 12 h. The reaction mixture was concentrated in vacuo toprovide an oil, which was subjected to column chromatography to yield4.0 g (19.7 mmol, 89%) of a mixture of 1- and3-allyl-5-nitrobenzimidazole. The nitrobenzimidazole mixture was stirredin 100 ml of MeOH for 12 under H₂ in the presence of 10% Pd/C. Thereaction mixture was filtered and concentrated in vacuo to provide oilyresidue which was subjected to column chromatography (50% Hexane/EtOAc)to provide 1.2 g (7.0 mmol) of 1-propyl-5-aminobenzimidazole and 1.1 9(6.4 mmol) of 3-propyl-5-aminobenzimidazole.

1-Propyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

Reaction of 1-propyl-5-aminobenzimidazole (1.2 g, 7.0 mmol) and ISA (2.2g, 16 mmol) provided 1.6 g (6.6 mmol, 94%) of the expected product aftercolumn chromatographic separation. The product obtained was converted tothe fumarate salt and recrystallized from MeOH to afford 2.1 g (76%) ofthe product as a light brown solid: mp 206-207° C.; Anal. Calc. forC₁₃H₁₇N₅.1.5C₄H40₄ requires C, 54.67; H, 5.55; N, 16.98. Found: C,54.60; H, 5.49; N, 17.16.

EXAMPLE 14 1-Propyl-4-bromo-5-(imidazolin-2-ylamino)Benzimidazole (#14)

1-Propyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-propyl-5-aminobenzimidazole (1.2 g, 7.1 mmol) in 10ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 0.83 g (3.4 mmol, 48%) of the product.

1-Propyl-4-bromo-5-(imidazolin-2-ylamino)Benzimidazole.

A reaction of the amine (0.83 g, 3.4 mmol) and ISA (1.3 g, 9.7 mmol)produced 0.44 g (1.3 mmol, 38%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.32 g (25%) of the product asa light brown solid: mp 206-207° C.; Anal. Calc. forC₁₃H₁₆N₅Br.0.5C₄H₄O₄.0.5H₂O requires C, 46.29; H, 4.92; N, 17.99. Found:C, 46.66; H, 4.86; N. 17.60.

Example 15 3-Propyl-5-(2-imidazolin-2-ylamino)Benzimidazole. (#15)

A reaction of 3-propyl-5-aminobenzimidazole (1.0 g, 5.8 mmol) and ISA(1.9 g, 14 mmol) provided 1.3 g (5.0 mmol, 87%) of product after columnchromatography. The product 35 obtained was converted to the fumaratesalt and recrystallized from isopropanol to afford 0.32 g (25%) of theproduct as a white solid: mp 198-199° C.; Anal. Calc. forC₁₃H₁₇N₅.1.0C₄H₄O₄ requires C, 56.82; H, 5.89; N, 19.49. Found: C,57.12; H, 5.91; N, 19.61.

Example 16 3-Propyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#16)

3-Propyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-propyl-5-aminobenzimidazole (0.71 g, 4.3 mmol) in 10ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 0.40 g (1.6 mmol, 37%) of the product.

3-Propyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 3-propyl-4-bromo-5-aminobenzimidazole (0.40 g, 1.6 mmol)and ISA (0.7 g, 5.2 mmol) provided 0.32 g (1.3 mmol, 81%) of productafter column chromatography. The product obtained was converted to thefumarate salt and recrystallized from isopropanol to afford 0.30 g (58%)of the product as a white solid: mp 179-181° C.; Anal. Calc. forC₁₃,H₁₆N₅Br 1.0C₄H₄O₄ requires C, 46.59; H, 4.60; N, 15.98. Found: C,46.36; H, 4.49; N, 15.81.

EXAMPLE 17 1-Isopropyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#17)

1- and 3-Isopropyl-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (4.8 g, 29 mmol) and isopropylbromide (3.7 ml) in a procedure described in Example 9 produces 5.1 g(23 mmol, 81%) of a mixture of 1- and 3-isopropyl-5-nitrobenzimidazole,which was converted to the corresponding amines in hydrogenation(H₂/Pd-C). The amine mixture was subjected to column chromatography (10%i-PrOH/CH₂Cl₂) to provide 1.5 g (7.9 mmol, 27%) of1-isopropyl-5-aminobenzimidazole and 2.4 g (12.6 mmol, 44%) of3-isopropyl -5-aminobenzimidazole.

1-Isopropyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

Reaction of 1-isopropyl-5-aminobenzimidazole (0.41 g, 2.3 mmol) and ISA(0.70 g, 5.2 mmol) provided 0.37 g (1.5 mmol, 66%) of the expectedproduct after column chromatographic separation. The product obtainedwas converted to the fumarate salt and recrystallized from isopropanolto afford 0.27 g (24%) of the product as a light brown solid: mp185-186° C.; Anal. Calc. for C₁₃H₁₇N₅.2.0C₄H₄O₄ requires C, 52.83; H,5.70; N,14.67. Found: C, 53.32; H, 5.63; N, 14.97.

EXAMPLE 18 1-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#18)

1-Isopropyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-isopropyl-5-aminobenzimidazole (2.4 g, 14 mmol) in 20ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 1.2 g (4.5 mmol, 35%) of the product.

1-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the amine (0.86 g, 3.4 mmol) and ISA (0.90 g, 6.7 mmol)produced 0.67 g (2.1 mmol, 61%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.55 g (37%) of the product asa light brown solid: mp 187-188° C.; Anal. Calc. forC₁₃H₁₆N₅Br.1.0C₄H₄O₄ requires C, 46.59; H, 4.60; N, 15.98. Found: C,46.35; H, 4.49; N, 15.82.

EXAMPLE 19 1-lsopropyl-4-Iodo-5-(2-imidazolin-2-ylamino)Benzimidazole(#19)

1-Isopropyl-4-iodo-5-aminobenzimidazole.

To a solution of 1-isopropyl-5-aminobenzimidazole (0.70 g, 3.7 mmol) andHg(OAc)₂ (2.1 g, 5.6 mmol) in 10 ml of AcOH was added solution of I₂ inAcOH until it produces a precipitation; The reaction mixture wasconcentrated in vacuo to provide a brown solid which was subjected tocolumn chromatography (5% NH₃ sat'd MeOH/CH₂Cl₂) to provide 0.40 g (1.3mmol, 35%) of the product.

1-Isopropyl-4-Iodo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the amine (0.40 g, 1.3 mmol) and ISA (0.5 g, 3.7 mmol)produced 0.18 g (0.48 mmol, 37%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.22 g (35%) of the product asa white solid: mp 208-209° C.; Anal. Calc. for C₁₃H₁₆N₅I.1.0C₄H₄O₄requires C, 42.08; H, 4.15; N, 14.43. Found: C, 41.86; H, 4.08; N,14.17.

EXAMPLE 20 3-Isopropyl-5-(2-imidazolin-2-ylamino)Benzimidazole. (#20).

A reaction of 3-isopropyl-5-aminobenzimidazole (1.0 g, 5.8 mmol) and ISA(1.5 g, 11 mmol) yielded 0.90 g (3.8 mmol, 65%) of product after columnchromatography. The product obtained was converted to the fumarate saltand recrystallized from isopropanol to afford 0.32 g (25%) of theproduct as a light brown solid: mp 206-207° C.; Anal. Calc. forC₁₃H₁₇N₅0.5C₄H₄O₄ requires C, 54.67; H, 5.55; N, 16.78. Found: C, 53.33;H, 5.50; N, 16.30.

EXAMPLE 21 3-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#21)

3-Isopropyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-isopropyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in20 ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 1.1 g (4.0 mmol, 47%) of the product.

3-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 3-isopropyl-4-bromo-5-aminobenzimidazole (1.1 g, 4.0 mmol)and ISA (1.2 g, 9.0 mmol) provided 0.60 g (1.9 mmol, 43%) of product,after column chromatography. The product obtained was converted to thefumarate salt and recrystallized from EtOH to afford 0.52 g (28%) of theproduct as a white crystal: mp 210-212° C.; Anal. Calc. forC₁₃H₁₆N₅Br.1.0C₄H₄O₄ requires C, 46.59; H, 4.60; N, 15.98. Found: C,46.60; H, 4.49; N, 15.74.

EXAMPLE 22 1-Isobutyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#22) 1-and 3-Isobutyl-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (4.8 g, 29 mmol) and isobutyl bromide(7.7 ml, 72 mmol) in a procedure described in Example 9 produces 5.3 g(24 mmol, 83%) of a mixture of 1- and 3-isopropyl-5-nitrobenzimidazole,which was converted to the corresponding amines in hydrogenation(H₂/Pd-C). The amine mixture was subjected to column chromatography (10%1-PrOH/CH₂Cl₂) to provide 1.8 g (9.4 mmol, 32%) of1-isobutyl-5-aminobenzimidazole and 2.7 g (14 mmol, 49%) of3-isobutyl-5-aminobenzimidazole.

1- Isobutyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

Reaction of 1-isobutyl-5-aminobenzimidazole (0.29 g, 1.2 mmol) and ISA(0.6 g, 4.5 mmol) provided 0.37 g (1.2 mmol, >95%) of the expectedproduct after column chromatographic separation. The product obtainedwas converted to the fumarate salt and recrystallized from isopropanolto afford 0.41 g (70%) of the product as a white solid: mp 185-186° C.;Anal. Calc. for C₁₄H₁₉N₅. 2.0C₄H₄O₄ requires C, 53.98; H, 5.56; N.14.31. Found: C, 53.85; H. 5.69; N, 14.22.

EXAMPLE 23

1-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#23)

1-Isobutyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-isobutyl-5-aminobenzimidazole (2.4 g, 13 mmol) in 20ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 1.2 g (4.5 mmol, 35%) of the product.

1-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of bromoamine (0.30 g, 1.1 mmol) and ISA (0.9 g, 6.7 mmol)produced 0.28 g (0.81 mmol, 73%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.28 g (56%) of the product asa white solid: mp 226-227° C.

EXAMPLE 24 3-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#24)

3-Isobutyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-isobutyl-5-aminobenzimidazole (1.5 g, 7.9 mmol) in 20ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 1.0 g (3.7 mmol, 29%) of the product.

3-Isobutyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 3-isobutyl-4-bromo-5-aminobenzimidazole (0.30 g, 1.1 mmol)and ISA (0.70 g, 5.2 mmol) provided 0.20 g (0.56 mmol, 51%) of theproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from isopropanol to afford 0.22g (45%) of the product as a white solid: mp 187-188° C.; Anal. Calc. forC₁₄H₁₈N₅Br.1.0C₄H₄,O₄ requires C, 47.80; H, 4.90; N, 15.48. Found: C,47.57; H, 4.61; N, 15.38.

EXAMPLE 25 1-Cyclopentyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#25)

1- and 3-Cyclopentyl-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (3.1 g, 19 mmol) and cyclopentylbromide (3.8 ml, 38 mmol) in a procedure described in Example 9 produces2.6 g (11 mmol, 59%) of a mixture of 1- and3-cyclopentyl-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10% i-PrOH/CH₂Cl₂) to provide 1.0 g(5.0 mmol, 45%) of 1-cyclopentyl-5-aminobenzimidazole and 1.1 g (5.4mmol, 50%) of 3-cyclopentyl-5-aminobenzimidazole.

1-Cyclopentyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 1-cyclopentyl-5-aminobenzimidazole (0.66 g, 3.3 mmol) andISA (1.3 g, 9.7 mmol) provided 0.91 g (2.7 mmol, 81%) of the expectedproduct after column chromatographic separation. The product obtainedwas converted to the fumarate salt and recrystallized from isopropanolto afford 1.1 g (77%) of the product as a white crystal: mp 214-215° C.;Anal. Calc. for C₁₅H₁₉N₅.1.5C₄H₄O₄ requires C, 56.88; H, 5.68; N, 15.79.Found: C, 56.69; H, 5.54; N, 16.02.

EXAMPLE 26 1-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#26) 1-Cyclopentyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-cyclopentyl-5-aminobenzimidazole (1.1 g, 5.5 mmol) in20 ml of AcOH was added solution of Br₂ in. AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 0.54 g (1.9 mmol, 35%) of the product.

1-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the amine (0.54 g, 1.9 mmol) and ISA (0.74 g, 5.5 mmol)produced 0.45 g (1.3 mmol, 67%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.32 g (19%) of the product asa light brown solid: mp 180-182° C.; Anal. Calc. forC₁₅H₁₈N₅Br.1.5C₄H₄O₄ requires C, 48.29; H, 4.63; N, 13.41. Found: C,48.56; H, 4.54; N, 13.23.

EXAMPLE 27 3-Cyclopentyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#27).

A reaction of 3-cyclopentyl-5-aminobenzimidazole (0.41 g, 2.0 mmol) andISA (0.68 g, 5.1 mmol) yielded 0.34 g (1.2 mmol, 62%) of product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from isopropanol to afford 0.28 g (31%)of the product as a white solid: mp 158-159° C.; Anal. Calc. forC₁₅H₁₉N₅.1.0C₄H₄O₄ requires C, 56.88; H, 5.68; N, 15.79. Found: C,55.69; H, 5.62; N, 15.73.

EXAMPLE 28 3-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#28)

3-Cyclopentyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-cyclopentyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in20 ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CH₂Cl₂) to provide 0.70 g (2.5 mmol, 50%) of the product.

3-Cyclopentyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 3-cyclopentyl-4-bromo-5-aminobenzimidazole (0.70 g, 2.5mmol) and ISA (0.94 g, 7.0 mmol) provided 0.26 g (0.78 mmol, 31%) ofproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from isopropanol to afford 0.31g (27%) of the product as a white solid: mp 208-210° C.; Anal. Calc. forC₁₅H₁₈N₅Br.1.0C₄H₄O₄ requires C, 49.15; H, 4.78; N, 15.08. Found: C,49.46; H, 4.88; N, 15.38.

EXAMPLE 29 1-Cyclohexylmethyl-5-(2-imidazolin-2-ylamino)Benzimidazole(#29)

1- and 3-Cyclohexylmethyl-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (3.1 g, 19 mmol) and cyclohexylmethylbromide (6.7 ml, 47 mmol) in a procedure described in Example 9 produces5.0 g (19 mmol, 100%) of a mixture of 1- and3-cyclohexylmethyl-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% hexane/EtOAc) to provide 2.0g (8.7 mmol, 45%) of 1-cyclohexylmethyl-5-aminobenzimidazole and 2.5 g(11 mmol, 54%) of 3-cyclohexylmethyl-5-aminobenzimidazole.

1-Cyclohexylmethyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 1-cyclohexylmethyl-5-aminobenzimidazole (2.2 g, 9.6 mmol)and ISA (3.6 g) provided 1.8 g (8.1 mmol, 84%) of the expected productafter column chromatographic separation. The product obtained wasconverted to the fumarate salt and recrystallized from isopropanol toafford 1.9 g (4.6 mmol, 48%) of the product as a white solid: mp222-223° C.; Anal. Calc. for C₁₇H₂₃N₅.1.0C₄H₄O₄ requires C, 61.00; H.6.58; N, 16.94. Found: C, 61.48; H, 6.41; N, 16.36.

EXAMPLE 301-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#30)

1-Cyclohexylmethyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-cyclohexylmethyl-5-aminobenzimidazole (2.5 g, 11mmol) in 20 ml of AcOH was added solution of Br₂ in AcOH until itproduces a precipitation. The reaction mixture was concentrated in vacuoto provide a brown solid which was subjected to column chromatography(5% NH₃ sat'd MeOH/CH₂Cl₂) to provide 1.37 g (4.3 mmol, 40%) of theproduct.

1-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the amine (1.4 g, 4.4 mmol) and ISA (1.8 g, 13 mmol)produced 1.6 g (4.1 mmol, 94%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 1.8 g (83%) of the product asa white solid: mp 193-195° C.; Anal. Calc. for C₁₇H₂₂N₅Br.1.0C₄H₄O₄requires C, 51.23; H, 5.32; N, 14.22. Found: C, 50.21; H, 5.17; N,14.29.

EXAMPLE 313-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#31)

3-Cyclohexylmethyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-cyclohexylmethyl-5-aminobenzimidazole (2.0 g, 8.7mmol) in 40 ml of AcOH was added solution of Br₂ in AcOH until itproduces a precipitation. The reaction mixture was concentrated in vacuoto provide a brown solid which was subjected to column chromatography(5% NH₃ sat'd MeOH/CHCl₃) to provide 1.2 g (3.8 mmol, 48%) of theproduct.

3-Cyclohexylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 3-cyclohexylmethyl-4-bromo-5-aminobenzimidazole (1.2 A,3.9 mmol) and ISA (1.5 g, 11 mmol) provided 0.85 g (2.3 mmol, 58%) ofproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from isopropanol to afford 1.1 g(51%) of the product as a white solid: mp 153-155° C.; Anal. Calc. forC₁₇H₂₂N₅Br.1.5C₄H₄O₄.0.5H₂O requires C, 49.38; H, 5.22; N, 12.58. Found:C, 49.22; H, 5.07; N, 12.19.

EXAMPLE 32 1-Benzyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#32)

1- and 3-Benzyl-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (3.0 g, 18 mmol) and benzyl bromide(4.4 ml, 37 mmol) in a procedure described in Example 9 produces 3.2 g(13 mmol, 71%) of a mixture of 1- and 3-benzyl-5-nitrobenzimidazole,which was converted to the corresponding amines in hydrogenation(H₂/Pd-C). The amine mixture was subjected to column chromatography(10%-30% Hexane/EtOAc) to provide 1.6 g (7.2 mmol, 55%) of1-benzyl-5-aminobenzimidazole and 1.2 g (5.3 mmol, 41%) of3-benzyl-5-aminobenzimidazole.

1-Benzyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 1-benzyl-5-aminobenzimidazole (0.35 g, 1.2 mmol) and ISA(0.42 g, 3.1 mmol) provided 0.17 g (0.46 mmol, 38%) of the expectedproduct after column chromatographic separation. The product obtainedwas converted to the fumarate salt and recrystallized from isopropanolto afford 0.11 g (20%) of the product as a white solid: mp 174-175° C.;Anal. Calc. for C₁₇H₁₇N₅.1.5C₄H₄O₄ requires C, 59.35; H, 4.98; N, 45.05.Found: C, 59.40; H. 4.81; N, 14.99.

EXAMPLE 33

1-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#33)

1-Benzyl-4-bromo-5-aminobenzimidazole.

To a solution of 1-benzyl-5-aminobenzimidazole (1.0 g, 5.0 mmol) in 40ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitate. The reaction mixture was concentrated in vacuo to provide abrown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CHC1₃) to provide 0.90g (2.5 mmol, 60%) of the product.

1-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of bromoamine(0.90 g, 3.0 mmol) and ISA (1.2 g, 8.9 mmol)produced 0.85 g (2.3 mmol, 77%) of the product after chromatographicseparation. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford l.1 g (70%) of the product asa white solid: mp 197-198° C.; Anal. Calc. for C₁₇H₁₆N₅Br.1.5C₄H₄O₄requires C, 50.75; H, 4.07; N, 12.87. Found: C, 50.91; H, 3.87; N,12.77.

EXAMPLE34 3-Benzyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#34).

A reaction of 3-benzyl-5-aminobenzimidazole (0.34 g, 1.6 mmol) and ISA(0.68 g, 5.1 mmol) yielded 0.43 g (1.3 mmol, 76%) of product aftercolumn chromatography. The product obtained was converted to thefumarate salt and recrystallized from isopropanol to afford 0.32 g (41%)of the product as a white solid: mp 174-175° C.; Anal. Calc. forC₁₇H₁₇N₅.1.5C₄H₄O₄ requires C, 59.35; H, 4.98; N, 15.05. Found: C,58.88; H, 5.19; N, 15.25.

EXAMPLE 35 3-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#35)

3-Benzyl-4-bromo-5-aminobenzimidazole.

To a solution of 3-benzyl-5-aminobenzimidazole (0.88 g, 3.9 mmol) in 20ml of AcOH was added solution of Br₂ in AcOH until it produces aprecipitation. The reaction mixture was concentrated in vacuo to providea brown solid which was subjected to column chromatography (5% NH₃ sat'dMeOH/CHCl₃) to provide 0.35 g (1.2 mmol, 29%) of the product.

3-Benzyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 3-benzyl-4-bromo-5-aminobenzimidazole(0.35 g, 1.2 mmol)and ISA (0.43 g, 3.2 mmol) provided 0.17 g (0.46 mmol, 38%) of theproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from MeOH to afford 0.12 g (21%)of the product as a white solid: mp 203-205° C.; Anal. Calc. forC₁₇H₁₆N₅Br.1.0C₄H₄O₄ requires C, 51.87; H, 4.64; N, 14.39. Found: C,S2.60; H, 4.73; N, 14.39.

EXAMPLE 361-(4-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#36)

1-(4-Methoxybenzyl)-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (4.3 g, 27 mmol) and 4-methoxybenzylchloride (4.3 ml, 30 mmol) in a procedure described in Example 9produces 5.6 g .(19 mmol, 73%) of a mixture of 1- and3-(4-methoxybenzyl) -5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% i-PrOH/CH₂Cl₂) to provide2.1 g (8.2 mmol, 43%) of 1-(4-methoxybenzyl)-5-aminobenzimidazole and2.4 g (9.2 mmol, 48%) of 3-(4-methoxybenzyl)-5-aminobenzimidazole.

1-(4-Methoxybenzyl)-4-bromo-5-aminobenzimidazole.

To a solution of 1-(4-methoxybenzyl)-5-aminobenzimidazole (0.80 g, 2.2mmol) in 20 ml of AcOH was added solution of Br₂ in AcOH until itproduces a precipitation. The reaction mixture was concentrated in vacuoto provide a brown solid which was subjected to column chromatography(5% NH₃ sat'd MeOH/CHCl₃) to provide 0.90 g (2.1 mmol, 95%) of theproduct.

1-(4-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the bromoamine (0.90 g, 2.1 mmol) and ISA (1.3 g, 9.7mmol) provided 1.0 g (2.0 mmol, 96%) of the product after columnchromatography.

EXAMPLE 371-(3-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#37)

1-(3-Methoxybenzyl)-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (2.5 g, 15 mmol) and 3-methoxybenzylchloride (2.6 ml, 17 mmol) in a procedure described in Example 9produces 1.0 g (3.1 mmol, 26%) of a mixture of 1- and3-(3-methoxybenzyl)-5-nitrobenzimidazole, which was converted to thecorresponding amines in hydrogenation (H₂/Pd-C). The amine mixture wassubjected to column chromatography (10%-30% isopropanol/CH₂Cl₂) toprovide 0.32 g (1.1 mmol, 36%) of3-(3-methoxybenzyl)-5-aminobenzimidazole and 0.37 g (1.3 mmol, 41%) of1-(3-methoxybenzyl)-5-aminobenzimidazole.

1- (3-Methoxybenzyl)-4-bromo-5-aminobenzimidazole.

To a solution of 1-(3-methoxybenzyl)-5-aminobenzimidazole (0.37 g, 1.3mmol) in 10 ml of AcOH was added solution of Br₂ in AcOH until itproduces a precipitation. The reaction mixture was concentrated in vacuoto provide a brown solid which was subjected to column chromatography(5% NH₃ sat'd Isopropanol/CHCl₃) to provide 0.31 g (1.0 mmol, 66%) ofthe product.

1- (3-Methoxybenzyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the bromoamine (0.31 g, 0.84 mmol) and ISA (0.52 g, 3.9mmol) provided 0.37 g (>95%) of product after column chromatography. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.36 g (83%) of the product as a whitecrystal: mp 177-178° C.; Anal. Calc. for C₁₈H₁₈N₅BrO.1.0C₄H₄O₄.H₂Orequires C, 48.63; H, 4.64; N, 12.89. Found: C, 48.06; H, 4.51; N,12.77.

EXAMPLE 381-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#38)

1- and 3-(2-Hydroxyethyl)-4-bromo-5-aminobenzimidazole.

A reaction of 5-nitrobenzimidazole (3.3 g, 20 mmol) and 2-hydroxyethylbromide (2.2 ml, 31 mmol) in a procedure described in Example 9 producesa mixture of 1- and 3-(2-hydroxyethyl)-5-nitrobenzimidazole, which wasconverted to the corresponding amines in hydrogenation (H₂/Pd-C) Theamine mixture (3.4 g, 19 mmol) in 50 ml of AcOH was added solution ofBr₂ in AcOH until it produces a precipitation. The reaction mixture wasconcentrated in vacuo to provide a brown solid which was subjected tocolumn chromatography (5% NH₃ sat'd isopropanol/CHCl₃) to provide 0.42 g(1.6 mmol) of 3-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole and 0.57 g(2.2 mmol, 11%) of 1-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole.

1-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 1-(2-hydroxyethyl)-4-bromo-5-aminobenzimidazole (0.25 g,1.4 mmol) and ISA (0.35 g, 2.6 mmol) provided 0.21 g (0.87 mmol, 62%) ofproduct after column chromatography. The product obtained was convertedto the fumarate salt and recrystallized from isopropanol to afford 0.17g (28%) of the product as a white solid: mp 141-143° C.; Anal. Calc. forC₁₂H₁₄N₅OBr.1.0C₄H₄O₄ requires C, 43.55; H, 4.12; N, 15.87. Found: C,44.14; H, 4.03; N, 15.53.

EXAMPLE 393-(2-Hydroxyethyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#39).

A reaction of 3-(2-hydroxy-1-ethyl)-4-bromo-5-aminobenzimidazole (0.31g, 1.8 mmol) and ISA (0.52 g, 3.9 mmol) provided 0.37.g (1.6 mmol, 88%)of the desired product after column chromatography.

The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 0.32 g (40%) of the product asa white solid: mp 217-218° C.

EXAMPLE 401-(2-Aminoethyl)-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#40).

To a solution of 1-(2-hydroxyethyl)-5-nitrobenzimidazole (0.27 g, 1.3mmol) was added triphenylphosphine (0.38 g, 1.4 mmol), DEAD (0.25 ml,1.4 mmol) and phthalimide (0.21 g, 1.4 mmol) in a portion and resultingmixture was stirred for 1 h at 25° C. The reaction mixture wasconcentrated in vacuo, yielding an oil which was subjected to columnchromatography (40% Hexane/EtOAc) to provide 0.36 g (1.1 mmol, 82%) of1-(2-phthalimidylethyl)-5-nitrobenzimidazole. The nitrobenzimidazole wassubsequently subjected to hydrogenation, bromination and coupling withISA to produce 0.41 g of1-(2-phthalimidylethyl)-4-bromo-5-(2-imidazolin-2-ylamino)benzimidazolewhich was refluxed with 0.3 ml of hydrazine in 20 ml of MeOH for 0.5 hto yield the desired product (0.31 g, 0.96 mmol, 68% overall). Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.21 g (24%) of the product as a white foamysolid.

EXAMPLE 41 2-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#41)

2-Methyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (1.0 g, 6.5 mmol) in 20 ml ofAcOH was stirred at ref lux for 12 h. Reaction mixture was concentratedin vacuo to yield a dark brown residue, which, in spectroscopicanalysis, corresponds to 2-methyl-5-nitrobenzimidazole and was subjectedto a following reaction without further purification. Thenitrobenzimidazole and 50 mg of 10% Pd/C were dissolved in 100 ml ofMeOH and stirred for 12 h under H₂. The reaction mixture was filteredand concentrated in vacuo yielding 0.95 g (6.5 mmol, >95%) of brown oilwhich was identified as 2-methyl-5-aminobenzimidazole in NMR and used ina following reaction without further purification.

2-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A 5 solution of the amine (0.70 g, 4.7 mmol) and ISA (0.8 g, 5.9 mmol)was stirred at reflux for 12 h. The reaction mixture was concentrated invacuo to yield an oily residue which was subjected to silica gel columnchromatography (NH₃ sat'd 20% MeOH/EtOAc) to yield 0.81 g (3.8 mmol,81%) of the desired product.

EXAMPLE 42 2-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#42)

2-Methyl-4-bromo-5-aminobenzimidazole.

To a solution of 0.9 g (6.1 mmol) of 2-methyl-5-aminobenzimidazole in 50ml of AcOH was added 0.16 ml of Br₂ (3.1 mmol) dropwise and resultingreaction mixture was stirred for 1 h at 25° C. Reaction mixture wasconcentrated in vacuo and purified on silica gel column chromatography(20% Isopropanol/EtOAC) to yield 0.56 g (2.5 mmol, 41%) of the desiredproduct.

2-Methyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

The amine (0.56 g, 2.5 mmol) and ISA (1.0 g, 7.4 mmol) were dissolved in5 ml of isobutanol and stirred at reflux for 12 h. The reaction mixturewas concentrated in vacuo and subjected to column chromatography (NH₃sat'd 20% Isopropanol/EtOAC) to yield 0.72 g (2.4 mmol, >99%) of theproduct. The product obtained was converted to the fumarate salt andrecrystallized from MeOH to afford 0.25 g (25%) of the product as awhite crystal: mp 222-224° C.; Anal. Calc. forC₁₁H₁₂N₅Br.1.0C₄H₄O₄.0.5H₂O requires C, 42.98; H, 4.09; N, 16.71. Found:C, 43.14; H, 4.03; N, 16.33.

EXAMPLE 43 2-Ethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#43)

2-Ethyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (1.0 g, 6.5 mmol) in 20 ml ofpropionic acid was stirred at reflux for 12 h. Reaction mixture wasconcentrated in vacuo to yield a dark brown residue, which, inspectroscopic analysis, corresponds to 2-ethyl-5-nitrobenzimidazole andwas subjected to a following reaction without further purification. Thenitrobenzimidazole and 50 mg of 10% Pd-C were dissolved in 100 ml ofMeOH and stirred for 12 h under H₂. The reaction mixture was filteredand concentrated in vacuo yielding 0.95 g (6.5 mmol, >95%) of brown oilwhich was identified as 2-ethyl-5-aminobenzimidazole in NMR and used ina following reaction without further purification.

2-Ethyl-4-bromo-5-aminobenzimidazole.

To a solution of 1.3 g (7.7 mmol) of 2-ethyl-5-aminobenzimidazole in 50ml of AcOH was added 0.40 ml of Br₂ (7.5 mmol) dropwise and resultingreaction mixture was stirred for 1 h at 25° C. The reaction mixture wasconcentrated in vacuo and purified on silica gel column chromatography(20% isopropanol/EtOAC) to yield 1.5 g (6.3 mmol, 82%) of the desiredproduct.

2-Ethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of 2-ethyl-4-bromo-5-aminobenzimidazole (1.5 g, 6.3 mmol)with ISA (2.3 g, 17 mmol) provides 1.4 g (4.5 mmol, 71%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from isopropanol to afford 1.53 g (61%) of the product asa white solid: mp 186-187° C.; Anal. Calc. for C₁₂H₁₄N₅Br.1.0C₄H₄O₄requires C, 45.30; H, 4.28; N, 16.51. Found: C, 45.03H, 4.11; N, 16.88.

EXAMPLE 44 2-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#44)

2-Isopropyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (0.9 g, 5.9 mmol) in 5 ml ofisobutyric acid was stirred at reflux for 12 h. The reaction mixture wasconcentrated in vacuo to yield a dark brown residue, which was dissolvedin 100 ml of EtOAc and washed with aqueous NaHCO₃. Organic layer wasdried over MgSO₄ and concentrated in vacuo, yielding an oil which wascharacterized as 2-isopropyl-5-nitrobenzimidazole and subjected to afollowing reaction without further purification. The nitrobenzimidazoleand 50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for12 h under H₂. The reaction mixture was filtered and concentrated invacuo, yielding 0.95 g (5.4 mmol, 92%) of the desired product.

2-Isopropyl-4-bromo-5-aminobenzimidazole.

To a solution of 0.95 g (5.4 mmol) of 2-isopropyl-5-aminobenzimidazolein 50 ml of AcOH was added 0.19 ml (3.7 mmol) of Br₂ dropwise andresulting reaction mixture was stirred for 1 h at 25° C. Reactionmixture was concentrated in vacuo and purified on silica gel columnchromatography (5% MeOH/EtOAC) to yield 0.89 g (3.5 mmol, 95%) of thedesired product.

2-Isopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the bromoamine (0.89 g, 3.5 mmol) and ISA (1.5 g, 11 mmol)provides 0.42 g (1.3 mmol, 37%) of the expected product. The productobtained was converted to the fumarate salt and recrystallized from EtOHto afford 0.43 g (28%) of the product as a light gray solid: mp 176-178°C.; Anal. Calc. for C₁₃H₁₆N₅Br. 1.0C₄H₄O₄ requires C, 46.59; H, 4.60; N,15.98. Found: C, 45.14; H, 4.39; N, 15.78.

EXAMPLE 45 2-tert-Butyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#45)

2-tert-Butyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (2.0 g, 13 mmol) in 10 ml oftrimethylacetic acid was stirred at reflux for 12 h. Reaction mixturewas concentrated in vacuo to yield a oil which was subjected to columnchromatography (CHCl₃, neat) to yield 2.2 g (10 mmol, 77%) of2-tert-butyl-5-nitrobenzimidazole. The nitrobenzimidazole and 0.5 g of10% Pd-C were dissolved in 100 ml of MeOH and stirred for 12 h under H₂.The reaction mixture was filtered and concentrated in vacuo to provide1.9 g (10 mmol, >95%) of the desired product.

2-tert-Butyl-4-bromo-5-aminobenzimidazole.

To a solution of 0.53 g (2.8 mmol) of 2-tert-butyl-5-aminobenzimidazolein 50 ml of AcOH was added 0.05 ml (1.0 mmol) of Br₂ dropwise andresulting reaction mixture was stirred for 1 h at 25° C. Reactionmixture was concentrated in vacuo and purified on silica gel columnchromatography (CHCl₃, neat) to yield 0.18 g (0.67 mmol, 67%) of thedesired product.

2-tert-Butyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the bromoamine (0.18 g, 0.67 mmol) and ISA (0.30 g, 2.2mmol) provides 0.21 g (0.62 mmol, 93%) of the product. The productobtained was converted to the fumarate salt and recrystallized from EtOHto afford 0.43 g (28%) of the product as a light gray solid: mp 176-178°C.; Anal. Calc. for C₁₄H₁₈N₅Br.1.0C₄H₄O₄ requires C, 47.48; H, 4.90; N,15.48. Found: C, 45.14; H, 4.39; N, 15.78.

EXAMPLE 462-Trifluoromethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#46)

2-Trifluoromethyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (3.0 g, 20 mmol) in 15 ml oftrifluoroacetic acid was stirred at reflux for 12 h. The reactionmixture was concentrated in vacuo to yield a oily residue, which wasdissolved in 100 ml of EtOAc and washed with aqueous NaHCO₃. The organiclayer was dried over MgSO₄ and concentrated in vacuo to provide an oilwhich was characterized as 2-trifluromethyl-5-nitrobenzimidazole andsubjected to the following reaction without further purification. Thenitrobenzimidazole and 500 mg of 10% Pd-C were dissolved in 100 ml ofMeOH and stirred for 12 h under H₂. The reaction mixture was filteredand concentrated in vacuo, yielding 3.2 g (16 mmol, 80%) of the desiredproduct.

2-Trifluoromethyl-4-bromo-5-aminobenzimidazole.

To a solution of 3.2 g (16 mmol) of2-trifluoromethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.34ml (6.6 mmol) of Br₂ dropwise and resulting reaction mixture was stirredfor 1 h at 25° C. The reaction mixture was concentrated in vacuo andpurified on silica gel column chromatography (10% MeOH/CHCl₃) to yield1.7 g (6.2 mmol, 94%) of the desired product.

2-Trifluoromethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

Reaction of the bromoamine (1.3 g, 4.6 mmol) and ISA (1.5 g) provided0.39 g (1.1 mmol, 23%) of the desired product. The product obtained wasconverted to the fumarate salt and recrystallized from EtOH to afford0.40 g (21%) of the product as a light brown solid: mp 231-232° C.

EXAMPLE 47 2-Cyclopropyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole(#47)

2-Cyclopropyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (1.0 g, 6.6 mmol) in 15 ml ofcyclopropanecarboxylic acid was stirred at reflux for 12 h. The reactionmixture was concentrated in vacuo to yield a oil, which was dissolved in100 ml of EtOAc and washed with aqueous NaHCO₃. Organic layer was driedover MgSO₄ and concentrated in vacuo, yielding an oil which wascharacterized as 2-cyclopropyl-5-nitrobenzimidazole and subjected to afollowing reaction without further purification. The nitrobenzimidazoleand 50 mg of 10% Pd-C were dissolved in 100 ml of MeOH and stirred for12 h under H₂. The reaction mixture was filtered and concentrated invacuo to provide 0.87 g (4.9 mmol, 75%) of the desired product.

2-Cyclopropyl-4-bromo-5-aminobenzimidazole.

To a solution of 0.87 g (4.9 mmol) of 2-cyclopropyl-5-aminobenzimidazolein 50 ml of AcOH was added 0.10 ml (1.9 mmol) of Br₂ dropwise andresulting reaction mixture was stirred for 1 h at 25° C. The reactionmixture was concentrated in vacuo and purified on silica gel columnchromatography (5% MeOH/EtOAC) to yield 0.42 g (1.8 mmol, >95%) of thedesired product.

2-Cyclopropyl-4-bromo-5- (2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the bromoamine (0.69 g, 2.4 mmol) and ISA (1.1 g, 8.2mmol) provides 0.71 g (2.2 mmol, 92%) of the desired product. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isobutanol to afford 0.62 g (62%) of the product as a light yellowsolid: mp 81-83° C.; Anal. Calc. for C₁₂H₁₄N₅Br.1.0C₄H₄O₄.1.0H₂Orequires C, 44.95; H, 4.44; N, 15.42. Found: C, 45.28; H, 4.35; N,14.94.

EXAMPLE 482-Diphenylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#48)

2-Diphenylmethyl-5-aminobenzimidazole.

A solution of 4-nitro-1,2-phenylenediamine (2 g, 13 mmol) in 10 g ofdiphenylacetic acid(neat) was stirred at reflux for 12 h. Reactionmixture was concentrated In vacuo to yield a dark brown residue, whichwas dissolved in 100 ml of EtOAc and washed with aqueous NaHCO₃. Organiclayer was dried over MgSO₄ and concentrated in vacuo, yielding an oilwhich was purified on column chromatography (50% Hexane/EtOAc) to yield1.7 g (5.3 mmol, 39%) of 2-diphenylmethyl-5-nitrobenzimidazole. Thenitrobenzimidazole and 250 mg of 10% Pd-C were dissolved in 100 ml ofMeOH and stirred for 12 h under H₂. The reaction mixture was filteredand concentrated in vacuo to provide 1.4 g (5.2 mmol, >95%) of thedesired product.

2-Diphenylmethyl-4-bromo-5-aminobenzimidazole.

To a solution of 1.1 g (3.7 mmol) of2-diphenylmethyl-5-aminobenzimidazole in 50 ml of AcOH was added 0.07 ml(1.3 mmol) of Br₂ dropwise and resulting reaction mixture was stirredfor 1 h at 25° C. Reaction mixture was concentrated in vacuo andpurified on silica gel column chromatography (5% MeOH/EtOAC) to yield0.42 g (1.1 mmol, 86%) of the desired product.

2-Diphenylmethyl-4-bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A reaction of the amine (1.1 g, 2.9 mmol) and ISA (1.5 g, 11 mmol)produces 0.51 g (1.1 mmol, 39%) of the expected product. The productobtained was converted to the fumarate salt and recrystallized from MeOHto afford 0.31 g (21%) of the product as a light brown solid: mp240-242° C.; Anal. Calc. for C₂₃H₂₀N₅Br.1.0C₄H₄O₄ requires C, 57.66; H,4.30; N, 12.45. Found: C, 57.58; H, 4.12; N, 12.28.

EXAMPLE 49 6-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#49)

6-Methyl-5-aminobenzimidazole.

To a solution of 20 ml of fuming nitric acid was added5-methylbenzimidazole (1.6 g, 12 mmol) slowly over 0.5 hand reactionmixture was stirred for 3 h at −15° C. During addition of substrate,reaction temperature was kept below −10° C. Sticky reaction mixture wasthen poured into ice water to form a yellow precipitation, which wascollected and dried in vacuo to provide 0.37 g (2.1 mmol, 17%) of5-methyl-6-nitrobenzimidazole. The nitrobenzimidazole was converted tothe corresponding amine (0.32 g, 95%) on hydrogenation (H₂, Pd/C).

6-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

The amine obtained above was stirred at reflux with ISA (0.96 g, 7.2mmol) in isobutanol for 12 h. Column chromatographic separation ofreaction mixture (NH₃ sat'd 30% MeOH/EtOAc) produced 0.40 g (1.6 mmol,78%) of the desired product. The product obtained was converted to thefumarate salt and recrystallized from EtOH to afford 0.43 g (63%) of theproduct as a white solid: mp 219-221° C.; Anal. Calc. forC₁₁H₁₃N₅.1.0C₄H₄O₄ requires C, 54.38; H, 5.17; N, 21.14. Found: C,54.14; H, 5.33; N, 20.84.

EXAMPLE 50 4,6-Dibromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#50).

To a solution of 4-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.2 g,0.7 mmol) in 10 ml AcOH was added 200 mg of Hg(OAc)₂ and few drops ofBr₂. Reaction mixture was concentrated in vacuo, yielding a dark oilyresidue, which was subjected to silica gel column chromatography (NH₃sat'd 30% MeOH/EtOAc) to provide 210 mg (0.58 mmol, 86%) of the desiredproduct. The product obtained was converted to the fumarate salt andrecrystallized from EtOH to afford 0.051 g (14%) of the product as awhite solid.

EXAMPLE 51 7-Bromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#51)

2,4-Dinitro-6-bromoaniline.

To a solution of 2,4-dinitroaniline (2.2 g, 12 mmol) in 40 ml of AcOHwas added 1.0 ml of Br₂ dropwise and reaction mixture was stirred for 1h. The reaction mixture was concentrated in vacuo, yielding a darkresidue which was diluted with EtOAc and washed with aqueous NaHCO₃.Organic layer was dried over MgSO₄ and concentrated in vacuo to provide2.9 g (11 mmol, 92%) of 2,4-dinitro-6-bromo-aniline which wascharacterized by NMR and used in a following reaction without furtherpurification.

4-Bromo-6-aminobenzimidazole.

A solution of 4.0 g of SnCl₂.2H₂O and 15 ml of HCl was added into2,4-dinitro-6-bromoaniline (1.8 g, 6.9 mmol) and resulting reactionmixture was stirred for 2 h at 25° C. The reaction mixture was thenbasified by adding 15% aq. NaOH and extracted with CHCl₃ several times.Combined extracts were dried over MgSO₄ and concentrated in vacuo toproduce 1.4 g (>95%) of corresponding amine. The amine was stirred atreflux in 10 ml of formic acid and 10 ml of acetic anhydride for 12 h.The reaction mixture was concentrated in vacuo, yielding oily residuewhich was stirred in 30 ml of HCl sat'd EtOH for 0.5 h. The oilyreaction mixture after concentration was subjected to columnchromatography (5% NH₃ sat'd MeOH/EtOAc) to yield 1.3 g (>95%) of thedesired product.

7-Bromo-5-(2-imidazolin-2-ylamino)Benzimidazole.

4-bromo-6-aminobenzimidazole (0.4 g, 1.9 mmol) and ISA (1.2 g, 8.9 mmol)was dissolved in isobutanol and stirred at reflux for 12 h. Columnchromatographic separation of the reaction mixture (NH₃ sat'd 20%MeOH/EtOAc) provided 0.41 g (1.5 mmol, 78%) of the product. The productobtained was converted to the fumarate salt and recrystallized fromisopropanol to afford 0.24 g (32%) of the product as a light brownsolid: mp 217-218° C.; Anal. Calc. for C₁₀H₁₀N₅Br.1.0C₄H₄O₄ requires C,42.44; H, 3.56; N, 17.68. Found: C, 42.28; H, 3.58; N, 17.40.

EXAMPLE 52 7-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#52)

4-Methyl-6-aminobenzimidazole.

To the solution of 4-bromo-6-aminobenzimidazole (0.85 g, 6.0 mmol) insealed tube with 10 ml of DMF was added tetramethyltin (1.7 ml, 12 mmol)and bis(triphenylphosphine)palladium(II) chloride (0.20 g). Theresulting reaction mixture was stirred for 12 h at 140° C. andconcentrated in vacuo, yielding oily residue which was subjected tocolumn chromatography (5% MeOH/CHCl₃)to produce 0.28 g (45%) of thedesired product.

7-Methyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of the amine (0.28 g, 1.8 mmol) and ISA (0.82 g, 6.2 mmol)was stirred at reflux for 24 h. The reaction mixture was subjected tocolumn chromatography (30% NH₃ sat'd MeOH/EtOAc) to yield 0.23 g (57%)of the product. The product obtained was converted to the fumarate saltand recrystallized from isopropanol to afford 0.24 g (40%) of theproduct as a light brown solid: mp 229-231° C.; Anal. Calc. forC₁₁H₁₃N₅.1.0C₄H₄O₄ requires C, 54.38; H, 5.17; N, 21.14. Found: C,54.02; H, 5.15; N, 20.48.

EXAMPLE 53 7-Chloro-5-(2-imidazolin-2-ylamino)Benzimidazole (#53)

4-chloro-6-aminobenzimidazole.

Methanolic solution of 6-chloro-2,4-dinitroaniline (2.4 g, 11 mmol) wasstirred overnight with 100 mg of 10% Pd/C under H₂. Reaction mixture wasfiltered and concentrated in vacuo to provide an oil which was dissolvedin 10 ml of acetic anhydride and 10 ml of formic acid and stirred atreflux for 12 h. The reaction mixture was concentrated in vacuo,yielding a brown oil which was characterized as4-chloro-6-foramidylbenzimidazole in NMR analysis. The foramide wasdissolved in 20 ml of HCl sat'd EtOH and stirred for 3h at 25° C. Thereaction mixture was purified in column chromatography (5% MeOH/EtOAc)to provide 0.89 g (5.3 mmol, 48% overall) of the desired product.

7-Chloro-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of 4-chloro-6-aminobenzimidazole (0.9 g, 5.4 mmol) and ISA(1.7 g, 13 mmol) was stirred at reflux for 24 h. Column chromatographicseparation of reaction mixture (30% NH₃ sat'd MeOH/EtOAc) provided 0.53g (2.2 mmol, 41%) of the product. The product obtained was converted tothe fumarate salt and recrystallized from MeOH to afford 0.41 g (22%) ofthe product as a light brown solid: mp 220-221° C.; Anal. Calc. forC₁₀H₁₀N₅Cl.1.0C₄H₄O₄ requires C, 47.81; H, 4.01; N, 19.91. Found: C,46.03; H, 4.14; N, 19.64.

EXAMPLE 54 7-Iodo-5-(2-imidazolin-2-ylamino)Benzimidazole (#54)

2,4-Dinitro-6-iodoaniline.

To a solution of 2,4-dinitroaniline (3.0 g, 16 mmol) and Hg(OAc)₂ (6.8g, 21 mmol) in 40 ml of AcOH was added 5.0 g (19 mmol) of I₂ in 100 mlof AcOH dropwise and reaction mixture was stirred for 12 h. The reactionmixture was concentrated in vacuo, yielding a dark residue which wasdiluted with EtOAc and washed with aqueous NaHCO₃. Organic layer wasdried over MgSO₄ and concentrated in vacuo to produce dark residue whichwas subjected to column chromatography (CHCl₃, neat) to provide 4.1 g(13 mmol, 81%) of 2,4-dinitro-6-iodoaniline.

7-Iodo-5-aminobenzimidazole.

A solution of 10 g of SnCl₂.2H₂O and 20 ml of HCl was added into2,4-dinitro-6-iodoaniline (4.1 g, 13 mmol) and resulting reactionmixture was stirred at reflux for 48 h. The reaction mixture was thenbasified by adding 15% aq. NaOH and extracted with CHCl₃ several times.Combined extracts were dried over MgSO₄ and concentrated in vacuo,yielding oily residue which was subjected to column chromatography (5%MeOH/EtOAc) to yield 1.1 g (4.4 mmol, 33%) of the amine. The amine wasstirred at reflux in 10 ml of formic acid and 10 ml of acetic anhydridefor 12 h. The reaction mixture was concentrated in vacuo to yield anoily residue which was stirred in 30 ml of HCl sat'd EtOH for 2 h. Theoily reaction mixture after concentration was subjected to columnchromatography (5% NH₃ sat'd MeOH/EtOAc) to provide 0.69 g (2.7 mmol,60%) of the desired product.

7-Iodo-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of 4-iodo-6-aminobenzimidazole (0.69 g, 2.7 mmol) and ISA(0.90 g, 6.7 mmol) was stirred at reflux for 12 h. Columnchromatographic separation (30% NH₃ sat'd MeOH/EtOAC) of resultingreaction mixture provided 0.88 g (>99%) of the product. The productobtained was recrystallized from isopropanol to afford 0.56 g (64%) ofthe product as a light brown solid: mp 180-181° C.

EXAMPLE 55 7-Ethyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#55)

2,4-Diamino-6-ethylaniline.

A solution of 2,4-dinitro-6-bromoaniline (1.6 g, 6.1 mmol),tetraethyltin (2.4 ml, 12.2 mmol) and Cl₂Pd(PPh₃)₂ (100 mg) in 10 ml ofDMF was stirred at 140° C. for 12 h. Reaction mixture was concentratedin vacuo, yielding an oil which was purified on silica gel columnchromatography (CH₂Cl₂, neat) to provide 0.68 g (3.2 mmol, 53%) of2,4-dinitro-6-ethylaniline, which was converted to the diamine (0.45 g,95%) on hydrogenation (H₂/Pd-C).

7-Ethyl-5-aminobenzimidazole.

The amine (0.46 g, 3.1 mmol) was stirred at reflux in formic acid for 12h. The reaction mixture was concentrated in vacuo to provide an oil,which was disolved in 50 ml of HCl sat'd EtOH and stirred for 1 h. Thereaction mixture was concentrated in vacuo, yielding an oil, which wassubjected to column chromatography (EtOAc, neat) to provide 0.23 g (1.5mmol, 47%) of the desired product.

7-Ethyl-5-(2-imidazolin-2-ylamino)Benzimidazole. The benzimidazole (0.23g, 1.5 mmol) and ISA (0.67 g, 5.0 mmol) was dissolved in isobutanol andstirred at reflux for 12 h. Column chromatographic separation ofreaction mixture (NH₃ sat'd 20% MeOH/EtOAc) provided 0.30 g (1.4 mmol,92%) of the product. The product obtained was converted to the fumaratesalt and recrystallized from isopropanol to afford 0.17 g (46%) of theproduct as a light brown solid: mp. 203-205° C.; Anal. Calc. forC₁₂H₁₅N₅.1.0C₄H₄O₄ requires C, 55.65; H, 5.55; N, 20.28. Found: C,55.90; H, 5.43; N, 19.87.

EXAMPLE 56 7-Butyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#56)

2,4-Diamino-6-butylaniline.

A solution of 2,4-dinitro-6-bromoaniline (2.0 g, 7.6 mmol),tetrabutyltin (5.3 ml, 15.2 mmol) and Cl₂Pd(PPh₃)₂ (100 mg) in 10 ml ofDMF was stirred at 140° C. for 12 h. Reaction mixture was concentratedin vacuo, yielding an oil which was purified on silica gel columnchromatography (CH₂Cl₂, neat) to provide 0.50 g (2.0 mmol, 27%) of2,4-dinitro-6-butylaniline, which was converted to the diamine (0.38g, >95%) on hydrogenation (H₂/Pd-C).

7-Butyl-5-aminobenzimidazole.

The amine (0.46 g, 3.1 mmol) was stirred at reflux in formic acid for 12h. reaction mixture was concentrated in vacuo to provide an oil, whichwas dissolved in 50 ml of HCl sat'd EtOH and stirred for 1 h. Thereaction mixture was concentrated in vacuo, yielding an oil, which wassubjected to column chromatography (EtOAc, neat) to provide 0.11 g (0.86mmol, 28%) of the desired product.

7-Butyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

The benzimidazole (0.11 g, 0.86 mmol) and ISA (0.25 g, 1.9 mmol) wasdissolved in isobutanol and stirred at reflux for 12 h. Columnchromatographic separation of reaction mixture (NH₃ sat'd 20%MeOH/EtOAc) provided 0.21 g (0.81 mmol, 95%) of the product. The productobtained was converted to the fumarate salt and recrystallized fromisopropanol to afford 0.17 g (45%) of the product as a light brownsolid: mp 115-117° C.; Anal. Calc. for C₁₄H₁₉N₅.1.5C₄H₄O₄ requires C,55.68; H, 5.84; N, 16.23. Found: C, 54.90; H. 5.84; N, 15.99.

EXAMPLE 57 7-Phenyl-5-(2-imidazolin-2-ylamino)Benzimidazole (#57)2,4-Diamino-6-phenylaniline.

A solution of 2,4-dinitro-6-bromoaniline (2.5 g, 9.5 mmol),tetramethyltin (6.1 g, 14.3 mmol) and Cl₂Pd(PPh₃)₂ (100 mg) in 10 ml ofDMF was stirred at 140° C. for 12 h. Reaction mixture was concentratedin vacuo, yielding an oil which was purified on silica gel columnchromatography (CH₂Cl₂, neat) to provide 1.0 g (3.8 mmol, 41%) of2,4-dinitro-6-phenylaniline, which was converted to the diamine (0.72g, >95%) on hydrogenation (H₂/Pd-C).

7-Phenyl-5-aminobenzimidazole.

The amine (0.72 g, 3.8 mmol) was stirred at reflux in formic acid for 12h. The reaction mixture was concentrated in vacuo to provide an oil,which was dissolved in 50 ml of HCl sat'd EtOH and stirred for 1 h. Thereaction mixture was concentrated in vacuo, yielding an oil, which wassubjected to column chromatography (EtOAc, neat) to provide 0.48 g (2.3mmol, 60%) of the desired product.

7-Phenyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

The benzimidazole (0.48 g, 2.3 mmol) and ISA (1.0 g, 7.5 mmol) wasdissolved in isobutanol and stirred at reflux for 12 h. Columnchromatographic separation of reaction mixture (NH₃ sat'd 20%MeOH/EtOAc) provided 0.64 g (0.23 mmol, >95%) of the product. Theproduct obtained was converted to the fumarate salt and recrystallizedfrom isopropanol to afford 0.25 g (24%) of the product as a light brownsolid: mp 149-151° C.; Anal. Calc. for C₁₆H₁₅N₅.1.5C₄H₄O₄ requires C,58.53; H, 4.69; N, 15.51. Found: C, 57.79; H, 4.80; N, 15.31.

EXAMPLE 58 4,7-Dibromo-5-(2-imidazolin-2-ylamino)Benzimidazole (#58)

To a solution of 7-bromo-5-(2-imidazolin-2-ylamino)benzimidazole (0.6 g,2.1 mmol) in 10 ml of AcOH was added Br₂ (0.057 ml, 1.1 mmol) in aportion. The resulting reaction mixture was stirred for 1 h at 25° C.Concentration of reaction mixture in vacuo yields a brown oil which wassubjected to column chromatography (30% NH₃ sat'd MeOH/EtOAc) toprovides 0.28 g (1.5 mmol, 71%) of the desired product. The productobtained was recrystallized from MeOH to afford 0.22 g (56%) of theproduct as a light brown solid: mp 320-321° C.; Anal. Calc. forC₁₀H₉N₅Br₂ requires C, 33.45; H, 2.53; N, 19.51. Found: C, 33.93; H,4.05; N, 19.01.

EXAMPLE 59 4-Bromo-7-methyl-5-(2-imidazolin-2-ylamino)Benzimidazole(#59)

4-Bromo-7-methyl-5-aminobenzimidazole.

A solution of 4,7-dibromo-5-aminobenzimidazole (1.5 g, 5.1 mmol) in 10ml of DMF was transferred into pressure bottle under Ar₂. To thesolution was added tetramethyltin (3.6 ml, 20 mmol) andbis(triphenylphosphine)palladium(II) chloride (200 mg). The resultingreaction mixture was stirred at 140° C. for 24 h and concentrated invacuo, yielding a dark oil which was subjected to column chromatography(40% EtOAC/CHCl₃) to yield 0.34 g (1.5 mmol, 290%) of the desiredproduct as well as 0.75 g of 4,7-dimethyl-5-aminobenzimidazole.

4-Bromo-7-methyl-5-(2-imidazolin-2-ylamino)Benzimidazole.

A solution of the amine (0.34 g, 1.5 mmol) and ISA (0.69 g, 5.1 mmol) in10 ml of isobutanol was stirred at reflux for 12 h. The resultingreaction mixture was purified on column chromatography (30% NH₃ sat'dMeOH/EtOAc) to yield 0.25 g (0.86 mmol, 57%) of the desired product. Theproduct obtained was recrystallized from MeOH to afford 0.13 g (30%) ofthe product as a light brown solid: mp 242-244° C.; Anal. Calc. forC₁₁H₁₂N₅Br requires C, 44.91; H, 4.11; N, 23.81. Found: C, 43.93; H,4.05; N, 23.01.

EXAMPLE 60 4-Bromo-7-chloro-5-(2-imidazolin-2-ylamino)Benzimidazole(#60).

To a solution of 7-chloro-5-(2-imidazolin-2-ylamino)benzimidazole (0.61g, 2.6 mmol) in 10 ml of AcOH was added 0.3 ml of Br₂. Resultingreaction mixture was stirred for 12 h at 25° C. and concentrated invacuo, yielding an oil, which was subjected to column chromatography(NH₃ sat'd 30% MeOH/EtOAc) to yield 0.23 g (0.85 mmol, 33%) of thedesired product. The product obtained was converted to the fumarate saltand recrystallized from MeOH to afford 0.12 g (12%) of the product as alight yellow solid: mp 244-246° C.; Anal. Calc. forC₁₀H₉N₅BrCl.1.0C₄H₄O₄.0.5H₂O requires C, 37.77; H, 3.17; N, 18.35.Found: C, 37.75; H, 3.08; N, 18.21.

Pharmacological Profiles of the Compounds in Cloned Human AdrenergicReceptors

Binding and functional assays were performed using stably transfectedhuman alpha adrenergic receptors. Equilibrium competition binding assayswere performed with membrane preparations from cultured LM(tk-) cellsstably transfected with the cloned human adrenoceptor subtypes exceptfor α_(2b), which was expressed in Y-1 cells, using [³H] prazosin for α₁receptors and [³H] rauwolscine for α₂ receptors.

EXAMPLE 61 Protocol for the Determination of the Potency of α₂ Agonists

The activity of the compounds at the different receptors was determinedin vitro using cultured cell lines that selectively express the receptorof interest. These cell lines were prepared by transfecting the clonedcDNA or cloned genomic DNA or constructs containing both genomic DNA andcDNA encoding the human alpha adrenergic receptors as described below.Table 1 shows the binding and functional activities at cloned humanalpha adrenergic receptors.

α_(2A) Human Adrenergic Receptor:

The entire coding region of α_(2A) (1350 bp), including 1.0kilobasepairs of 5′ untranslated sequence (5′ UT) and 100 bp of 3′untranslated sequence (3′ UT), was cloned into the Smal site of theeukaryotic expression vector pCEXV-3. The insult housing this codingregion was an @ 2.5 kb Kpnl/HindIII human placenta genomic fragmentwhich was end-blunted by either T₄ polymerase or Klenow fragment of DNApolymerase. Stable cell lines were obtained by cotransfection with thePlasmid pGCcos3neo (plasmid containing the α_(2A) receptor gene) and theplasmid pGCcos3neo (plasmid containing the aminoglycoside transferasegene) into LM(tk-), CHO, and NIT3T3 cells, using calcium phosphatetechnique. The cells were grown, in a controlled environment (37° C., 5%CO₂), as monolayers in Dulbecco's modified Eagle's Medium (GIBCO, GrandIsland, N.Y.) containing 25 mM glucose and supplemented with 10% bovinecalf serum, 100 units/ml penicillin g, and 100 μg/ml streptomycinsulfate. Stable clones were then selected for resistance to theantibiotic G-418 (1 mg/ml), and membranes were harvested and assayed fortheir ability to bind [³H] rauwolscine as described below (see“Radioligand Binding Assays”).

α_(2B) Human Adrenergic Receptor:

The entire coding region of α_(2B) (1350 bp), including 393 bp of 5′untranslated sequence and 11 bp of 3′ untranslated sequence, was clonedinto the eukaryotic expression vector pcEXV-3 (Weinshank et al, U.S.Pat. No. 5,053,337, issued Oct. 1, 1991). Stable cell lines wereselected as described above.

α_(2C) Human Adrenergic Receptor:

The entire coding region of α_(2C) (1383 bp), including 2 bp of 5′ UTand 400 bp of 3′ UT, was cloned into the Smal site of the eukaryoticexpression vector pCEXV-3. The insert housing this coding region was an@ 1.8 kb Ncol/EcoRI human spleen genomic fragment which was end-bluntedby either T₄ polymerase or Klenow fragment of DNA polymerase. Stablecell lines were selected as described above.

Radioligand Binding Assays:

Transfected cells from culture flasks were scraped into 5 ml of 5 mMTris-HCl, 5 mM EDTA, pH 7.5, and lysed by sonication. The cell lysateswere centrifuged at 1000 rpm for 5 min at 4° C., and the supernatant wascentrifuged at 30,000×g for 20 min at 4° C. The pellet was suspended in50 mM Tris-HCl, 1 mM MgCl₂, and 0.1% ascorbic acid at pH 7.5. Binding ofα₂ antagonist [³H] rauwolscine (0.5 mM) to membrane preparations ofLM(tk-) cells was done in a final volume of 0.25 ml and incubated at 37°C. for 20 min. Nonspecific binding was determined in the presence of 10μM phentolamine. The reaction was stopped by filtration through GF/Bfilters using a cell harvester. Inhibition experiments, routinelyconsisting of 7 concentrations of the tested compounds, were analyzedusing a non-linear regression curve-fitting computer program to obtainKi values.

Measurement of Agonist Activity:

The agonist activity (expressed as pEC₅₀) was measured as a function ofthe ability to inhibit the forskolin-stimulated synthesis of cyclicadenosine monophosphate (cAMP). The stably transfected cells wereincubated in Ham's F10 with 5 mM theophylline, 10 mM HEPES, 10 μMpargyline, and/or appropriate concentrations of forskolin for 20 min at37° C. in 5% CO₂. The tested compounds were then added to a finalconcentration of 0.001 nM to 1 μM and incubated for an additional 15 minat 37° C. in 5% CO₂. The medium was aspirated and the reaction wasstopped by the addition of 100 mM HCl . To demonstrate competitiveantagonism, a dose-response curve for norepinephrine was measured inparallel, using a fixed dose of norepinephrine(0.32 μM). The plates arestored at 4° C. for 15 min and assayed to determine the linearconcentration of cAMP. The appropriate dilution is interpolated from thestandard curve of cold cAMP. The assessment of cAMP formation isdetermined by radioimmunoassay (cAMP radioimmunoassay kit; AdvancedMagnetics, Cambridge, Mass.). Radioactivity was quantified using aPackard COBRA Auto Gamma counter, equipped with data reduction software.

α_(1A) Human Adrenergic Receptor:

The entire coding region of α_(1A) (1719 bp), including 150 bp of 5′untranslated sequence (5′ UT) and 300 bp of 3′ untranslated sequence (3′UT), was cloned into the BamHI and ClaI sites of the polylinker-modifiedeukaryotic expression vector pCEXV-3, called EXJ.HR (Bard et al,International Publication No. WO 94/08040, published Apr. 14, 1994). Theconstruct involved the ligation of partial overlapping human lymphocytegenomic and hippocampal cDNA clones: 5′ sequences were contained on a1.2 kb SmaI-XhoI genomic fragment (the vector-derived BamHI site wasused for subcloning instead of the internal insert-derived Smal site)and 3′ sequences were contained on 1.3 kb XhoI-ClaI cDNA fragment (theClaI site was from the vector polylinker). Stable cell lines wereselected as described above.

α_(1B) Human Adrenergic Receptor:

The entire coding region of α_(1B)(1563 bp), including 200 basepairs and5′ untranslated sequence (3′ UT) and 600 bp of 3′ untranslated sequence(3′ UT), was cloned into the EcoRI, site of pCEXV-3 eukaryoticexpression vector (Bard et al, International Publication No. WO94/08040, published Apr. 14, 1994). The construct involved ligating thefull-length containing EcoRI brainstem cDNA fragment from ZapII into theexpression vector. The stable cell lines were selected as describedabove.

α_(1C) Human Adrenergic Receptor:

The entire coding region of α_(1C) (1401 bp), including 400 basepairs of5′ untranslated sequence (5′ UT) and 200 p of 3′ untranslated sequences(3′ UT), was cloned into the KpnI site of the polylinker-modifiedpCEXV-3-derived eukaryotic expression vector, EXJ.RH (Bard et al,International Publication No. WO 94/08040, published Apr. 14, 1994). Theconstruct involved ligation three partial overlapping fragments: a 5′0.6 kb HincII genomic clone, a central 1.8 EcoRI hippocampal cDNA clone,and a 3′ 0.6 Kb PstI genomic clone. The hippocampal cDNA fragmentoverlaps with the 5′ and 3′ genomic clones so that the HincII and PstIsites at the 5 and 3′ ends of the cDNA clone, respectively, wereutilized for ligation. This full-length clone was cloned into the KpnIsite of the expression vector, using the 5′ and 3′ KpnI sites of thefragment, derived from vector (i.e., pBluescript) and 3′-untranslatedsequences, respectively. Stable cell lines were selected as describedabove.

TABLE 1 Binding and Functional Activities at Cloned HumanAlpha-Adrenergic Receptors Alpha-2 Alpha-1 Ex A B C A B C  1 pKi 7.747.13 7.15 5.17 4.61 5.28 pEC50 7.24 7.35 8.56 I.A 1.00 1.00 1.00  2 pKi8.41 7.69 7.01 6.02 5.23 5.77 pEC50 9.S3 7.73 6.93 I.A 1.00 1.00 1.00  3pKi 6.12 7.81 7.00 6.27 5.09 5.72 pEC50 9.18 7.90 9.25 I.A 1.00 1.001.00  4 pKi 8.S1 8.04 7.59 6.22 5.56 6.14 pEC50 9.41 8.01 9.45 I.A 1.001.00 1.00  5 pKi 8.45 7.51 7.62 6.27 5.74 5.65 pEC50 9.0S 7.33 8.87 I.A1.00 1.00 1.00  6 pKi 8.33 7.65 7.32 ND ND ND pEC50 8.17 7.65 8.40 I.A1.00 1.00 1.00  7 pKi 8.45 7.5S 7.38 6.57 5.91 5.7S pEC50 8.14 6.70 8.21I.A 1.00 1.00 1.00  8 pKi 7.59 7.30 6.92 6.17 5.58 5.7S pEC50 6.87 6.637.68 I.A 0.90 0.80 1.00  9 pKi 7.74 7.33 6.81 5.56 4.87 5.17 pEC50 6.657.23 7.92 I.A 1.00 1.00 1.00 10 pKi 8.23 7.55 7.81 6.21 5.42 6.07 pEC508.52 6.99 8.63 I.A 1.00 1.00 1.00 11 pKi 7.09 6.65 5.95 5.00 4.45 5.24pEC50 NA NA NA I.A 12 pKi 8.20 7.84 7.59 7.02 6.46 6.46 pEC50 7.27 7.517.76 I.A 1.00 1.00 1.00 13 pKi 7.85 6.44 6.40 4.98 4.03 S.S3 pEC50 NA NANA I.A 14 pKi 8.02 6.66 6.64 5.63 4.69 6.21 pEC50 6.60 NA NA I.A 1.00 15pKi 6.94 6.14 6.06 5.19 4.46 5.31 pEC50 NA NA NA I.A 16 pKi 8.2S 7.917.38 7.26 6.29 6.38 pEC50 6.40 NA NA I.A 1.00 17 pKi 7.39 6.18 6.08 4.984.35 5.04 pEC50 NA NA NA I.A 1.00 18 pKi 8.35 6.43 6.55 5.57 4.70 6.05pEC50 7.08 NA NA I.A 0.80 19 pKi 8.33 6.67 6.89 ND ND ND pEC50 6.31 NANA I.A 0.70 20 pKi 6.62 6.14 6.20 4.83 4.23 4.95 pEC50 NA NA NA I.A 21pKi 8.19 7.67 7.26 6.13 5.33 5.92 pEC50 6.60 NA NA I.A 0.90 22 pKi 8.106.37 6.74 4.98 3.98 5.73 pEC50 NA NA NA I.A 23 pKi 7.90 6.51 6.64 5.304.42 6.42 pEC50 6.16 NA NA I.A 0.90 24 pKi 8.48 7.89 7.47 6.51 5.31 6.60pEC50 7.34 NA NA I.A 1.00 25 pKi 7.79 6.19 6.36 5.21 4.35 5.01 pEC50 NANA NA I.A 26 pKi 7.93 6.25 6.59 5.05 4.24 5.02 pEC50 NA NA NA I.A 27 pKi7.03 5.99 6.14 5.08 4.47 5.16 pEC50 NA NA I.A 28 pKi 8.41 7.38 7.02 6.184.98 5.42 pEC50 NA NA NA I.A 29 pKi 7.58 6.44 6.31 6.04 4.68 5.85 pEC50NA NA NA I.A 30 pKi 7.76 6.78 6.51 ND ND ND pEC50 NA NA NA I.A 31 pKi8.18 7.43 7.41 6.59 5.67 6.43 pEC50 NA NA NA I.A 32 pKi 7.96 7.30 6.795.43 4.48 5.41 pEC50 NA NA NA I.A 33 pKi 8.47 7.86 6.79 5.74 4.48 5.84pEC50 NA NA NA I.A 34 pKi 7.42 7.05 6.73 5.59 4.92 5.87 pEC50 NA NA NAI.A 35 pKi 8.46 7.80 7.77 6.51 5.71 6.10 pEC50 NA NA NA I.A 36 pKi 8.026.97 6.78 6.09 4.96 5.19 pEC50 8.26 6.55 NA I.A 0.60 0.60 37 pKi 8.187.09 6.93 ND ND ND pEC50 7.69 NA 7.28 I.A 0.60 0.50 38 pKi 7.41 6.285.89 5.14 4.76 5.17 pEC50 7.45 6.80 6.44 I.A 1.00 0.80 1.00 39 pKi 7.366.31 6.21 5.80 4.96 5.32 pEC50 7.61 NA NA I.A 0.90 40 pKi 6.40 6.02 5.555.03 4.57 5.04 pEC50 6.14 NA NA I.A 0.80 42 pKi 7.99 7.63 6.67 5.79 5.075.09 pEC50 7.63 7.01 NA I.A 1.00 0.60 43 pKi 8.14 7.47 6.74 5.76 5.165.67 pEC50 7.64 6.79 7.09 I.A 1.00 0.80 0.90 44 pKi 8.53 7.33 6.67 5.695.23 5.51 pEC50 8.40 7.04 6.74 I.A 1.00 0.80 0.80 45 pKi 8.07 7.08 6.535.34 4.94 5.66 pEC50 7.28 6.07 7.92 I.A 1.00 0.70 0.60 46 pKi 7.34 6.985.83 5.15 4.55 4.97 pEC50 7.41 6.23 7.19 I.A 1.00 0.80 0.90 47 pKi 8.177.35 6.65 ND ND ND pEC50 7.33 6.94 7.34 I.A 1.00 0.80 0.80 48 pKi 7.116.18 6.61 5.91 7.31 6.92 pEC50 NA 6.70 8.87 I.A 0.80 0.60 49 pKi 7.717.44 6.67 ND ND ND pEC50 7.04 NA 7.65 I.A 0.80 1.00 50 pKi 8.16 8.637.61 7.45 6.78 6.11 pEC50 7.80 7.68 7.15 I.A 1.00 0.90 1.00 51 pKi 7.587.56 6.91 ND ND ND pEC50 7.01 7.05 8.37 I.A 0.90 0.60 1.00 52 pKi 7.617.11 6.90 ND ND ND pEC50 7.09 7.14 8.26 I.A 0.90 0.80 1.00 53 pKi 7.837.74 7.05 6.51 5.72 6.00 pEC50 7.24 7.74 8.97 I.A 1.00 1.00 1.00 54 pKi7.31 7.56 6.70 ND ND ND pEC50 5.90 6.86 7.69 I.A 0.70 0.60 0.90 55 pKi7.36 6.68 6.37 ND ND ND pEC50 7.29 NA 6.79 I.A 0.60 0.80 56 pKi 7.666.74 6.69 5.90 5.29 6.23 pEC50 6.30 6.66 7.89 I.A 0.70 0.30 1.00 57 pKi7.78 7.22 6.87 ND ND ND pEC50 NA 5.07 7.82 I.A 0.50 1.00 58 pKi 8.896.76 7.51 ND ND ND pEC50 8.61 7.55 8.49 I.A 1.00 0.50 1.00 59 pKi 9.018.10 7.78 ND ND ND pEC50 9.08 7.39 8.89 I.A 1.00 0.90 1.00 60 pKi 9.059.33 7.79 6.65 6.5 6.32 pEC50 9.23 7.75 9.4 I.A 1 0.9 1 C pKi 8.03 8.097.52 6.29 5.62 6.01 pEC50 8.09 6.79 7.26 I.A 1 1 1 NA: Not Active ND:Not Determined C: Clonidine

The protocols used to obtain these data are described in Example 61.

EXAMPLE 62 Assay to Measure Analgesic Activity of Test Compounds

Warm-Water Tail Withdrawal Assay (Butelman, E. R.; Woods, J. H. J.Pharmacol. Exp. Therapeut. 1993, 264, 7620)

Subjects. Adult rhesus monkeys (Macaca mulatta) of either sex werehoused individually with free access to water. They were fed fresh fruitweekly and approximately 40 biscuits (Purina Monkey Chow) daily.

Apparatus and procedure. Tail withdrawal latencies were timed manuallyusing a microprocessor (IBM PCjr) via a push button switch. Monkeys wereseated in primate restraining chairs, and the lower portion of theshaved tail (approximately 10 cm) was immersed in a thermos flaskcontaining water maintained at either 40, 50 or 55° C. A maximum allowedlatency of 20 seconds was recorded if the monkeys failed to remove theirtails by this time. Sessions began with control determinations at eachwater temperature, presented in a varied order between the subjects. Inorder for a subject to be used, its withdrawal latency at 40° C. had toreach 20 seconds. After control determinations, drugs were administeredevery 30 minutes using a cumulative dosing procedure in which dosesincreased in 0.25 or 0.5 log units with each cycle. Fifteen minutesafter each injection, the subjects were tested at the three temperaturesin varying order, with tests being separated from each other byapproximately 2 minutes. In time course studies, a single drug dose wasadministered after control determination, with testing following at 30minute intervals.

Design. Clonidine and compound 4 were studied up to doses that producednear maximal withdrawal latencies in 55° C. water. The same threesubjects were studied in all the above experiments.

Sedation and Muscle Relaxation.

Procedure. Monkeys were trained to receive subcutaneous injections whilein their home cages; they were rated by one non-blind observer familiarwith the individual subjects, according to modified rating scales forsedation and muscle relaxation (Table 2); Separate scales describeincreasing degrees of sedation (as measured by responsiveness tostimuli) and muscle relaxation (as observed through changes in posture).Animals were injected in a cumulative dosing procedure with a 30 minuteinterinjection interval; observer rating on both scales took placeapproximately 15 minutes after each injection.

Design. Clonidine (0.032-1.0 mg/kg) and compound 4 (0.1-3.2 mg/kg) werestudied using a cumulative dosing procedure. The same three monkeys weretypically studied under each se of conditions.

Results: Using the procedures described above, compound 4 was found tobe an effective analgesic agent with decreased sedation relative to thereference compound, clonidine.

TABLE 2 Modified sedation and muscle relaxation rating scales GradeSedation 0 No observable sedation 1 Monkey appears to stare into space 2Monkey is inattentive to ordinary movements of observer 3 Monkeyresponds only to loud noises in the room 4 Monkey responds only toopening of cage latch 5 Monkey responds only to loud noises near its ear6 Monkey responds only to touch Muscle Relaxation 0 No observable musclerelaxation 1 Slight facial relaxation, jaw slackening, shoulder droop 2Pronounced facial relaxation, jaw slackening, shoulder droop 3 Monkeymust brace itself to sit up 4 Monkey cannot sit up

What is claimed is:
 1. A method for treating an alpha-2 adrenergicreceptor associated disorder in a subject which comprises administeringto the subject an amount of a compound effective to treat the disorder,wherein the compound has the structure:

wherein each of R₁, R₃ and R₉ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl or substitutedphenyl; wherein R₂ is straight chain or branched, substituted orunsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl orcycloalkenyl; or phenyl or substituted phenyl; wherein each dashed linerepresents a single bond or a double bond with the proviso that if R₁ ispresent, R₃ is absent and there is a double bond between N at position 3and C at position 2 and a single bond between C at position 2 and N atposition 1 and if R₃ is present, R₁ is absent, there is a double bondbetween N at position 1 and C at position 2 and a single bond between Cat position 2 and N at position 3; wherein R₄ is F, Cl, Br, I; straightchain or branched, substituted or unsubstituted C₂-C₇ alkynyl; C₃-C₇cycloalkyl or cycloalkenyl; or phenyl, substituted phenyl, —COR₇,—CO₂R₇, —CON(R₇)₂,—OCOR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇,—(CH₂)_(n)N(R₇)₂, or —(CH₂)_(n)NR₇COR₇, wherein n is an integer from 1to 4; wherein R₅ is H; wherein R₆ is H, F, Cl, Br, I; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl, substitutedphenyl, —OH, —OR₇, —CN, —COR₇, —CO₂R₇, —CON(R₇)₂, —OCOR₇, —SR₇, —N(R₇)₂,—NR₇COR₇, —(CH₂)_(n)OR₇, —(CH₂)_(n)N(R₇)₂, or —(CH₂)_(n)NR₇COR₇; whereineach of R₇ and R₈ is independently H; straight chain or branched,substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; orphenyl or substituted phenyl; and wherein any substitutent if present isselected from a group consisting of F, —NH₂, —OH, cyclohexyl, phenyl, ormethoxyphenyl.
 2. A method for treating an alpha-2 adrenergic receptorassociated disorder in a subject which comprises administering to thesubject an amount of a compound effective to treat the disorder, whereinthe compound has the structure:

wherein R₁ is H; straight chain or branched, substituted orunsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl orcycloalkenyl; or phenyl or substituted phenyl; wherein R₂ is straightchain or branched, substituted or unsubstituted C₁-C₇ alkyl, or C₂-C₇alkenyl or alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl orsubstituted phenyl; wherein R₄ is F, Cl, Br, I; straight chain orbranched, substituted or unsubstituted C₂-C₇ alkynyl; C₃-C₇ cycloalkylor cycloalkenyl; or phenyl, substituted phenyl, —COR₇, —CO₂R₇,—CON(R₇)₂, —OCOR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇, —(CH₂)_(n)N₇(R)₂,or —(CH₂)_(n)NR₇COR₇, wherein n is an integer from 1 to 4; wherein R₆ isH, F, Cl, Br, I; straight chain or branched, substituted orunsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; C₃-C₇ cycloalkyl orcycloalkenyl; or phenyl, substituted phenyl, —OH, —OR₇, —CN, —COR₇,—CO₂R₇, —CON(R₇)₂, —OCOR₇, —SR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇,—(CH₂)_(n)N(R₇)₂, or —(CH₂)_(n)NR₇COR₇; wherein each R₇ is independentlyH; straight chain or branched, substituted or unsubstituted C₁-C₇ alkyl,C₂-C₇ alkenyl or alkynyl; or phenyl or substituted phenyl; and whereinany substitutent if present is selected from a group consisting of F,—NH₂, —OH, cyclohexyl, phenyl, or methoxyphenyl.
 3. A method fortreating an alpha-2 adrenergic receptor associated disorder in a subjectwhich comprises administering to the subject an amount of a compoundeffective to treat the disorder, wherein the compound has the structure:

wherein each of R₁, R₂, and R₃ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl or substitutedphenyl; wherein each dashed line represents a single bond or a doublebond with the proviso that if R₁ is present, R₃ is absent and there is adouble bond between N at position 3 and C at position 2 and a singlebond between C at position 2 and N at position 1 and if R₃ is present,R₁ is absent and there is a double bond between N at position 1 and C atposition 2 and a single bond between C at position 2 and N at position3; wherein R₄ is independently H, F, Cl, Br, I; straight chain orbranched, substituted or unsubstituted C₂-C₇ alkynyl; C₃-C₇ cycloalkylor cycloalkenyl; or phenyl, substituted phenyl, —OH, —OR₇, —CN, —COR₇,—CO₂ R₇, —CON(R₇)₂, —OCOR₇, —SR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇,—(CH₂)_(n)N(R₇)₂, or —(CH₂)_(n)NR₇COR₇; wherein each of R₅ and R₆ isindependently H, F, Cl, Br, I; straight chain or branched, substitutedor unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl and alkynyl; C₃-C₇cycloalkyl or cycloalkenyl; or phenyl, substituted phenyl, —OH, —OR₇,—CN, —COR₇, —CO₂R₇, —CON(R₇)₂, —OCOR₇, —SR₇,—N(R₇)₂, —NR₇COR₇,—(CH₂)_(n)OR₇, —(CH₂)_(n)N(R₇)₂, or —(CH₂)_(n)NR₇COR₇; wherein n is aninteger from 1 to 4; with the proviso that if R₄ is H, F, Cl, Br, or I,then one of R₁, R₂, R₃, or R₆ is not H; wherein R₇ is independently H;straight chain or branched, substituted or unsubstituted C₁-C₇ alkyl,C₂-C₇ alkenyl or alkynyl; or phenyl or substituted phenyl; and whereinany substituent if present is selected from a group consisting of F,—NH₂, —OH, cyclohexyl, phenyl, or methoxyphenyl.
 4. A method fortreating an alpha-2 adrenergic receptor associated disorder in a subjectwhich comprises administering to the subject an amount of a compoundeffective to treat the disorder, wherein the compound has the structure:

wherein each of R₁ and R₃ is independently H; straight chain orbranched, substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl oralkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl or substitutedphenyl; wherein R₂ is independently straight chain or branched,substituted or unsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl;C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl or substituted phenyl;wherein each dashed line represents a single bond or a double bond withthe proviso that if R₁ is present, R₃ is absent and there is a doublebond between N at position 3 and C at position 2 and a single bondbetween C at position 2 and N at position 1 and if R₃ is present, R₁ isabsent and there is a double bond between N at position 1 and C atposition 2 and a single bond between C at position 2 and N at position3; wherein each of R₄, R₅ and R₆ is independently H, F, Cl, Br, I;straight chain or branched, substituted or unsubstituted C₁-C₇ alkyl,C₂-C₇ alkenyl and alkynyl; C₃-C₇ cycloalkyl or cycloalkenyl; or phenyl,substituted phenyl, —OH, —OR₇, —CN, —COR₇, —CO₂R₇, —CON(R₇)₂, —OCOR₇,—SR₇, —N(R₇)₂, —NR₇COR₇, —(CH₂)_(n)OR₇, —(CH₂)_(n)N(R₇)₂, or—(CH₂)_(n)NR₇COR₇; wherein n is an integer from 1 1to 4; wherein R₇ isindependently H; straight chain or branched, substituted orunsubstituted C₁-C₇ alkyl, C₂-C₇ alkenyl or alkynyl; phenyl orsubstituted phenyl; and wherein any substitutent if present is selectedfrom a group consisting of F, —NH₂, —OH, cyclohexyl, phenyl, ormethoxyphenyl.
 5. The method of claim 1, 2, 3, or 4, wherein thedisorder is pain.
 6. The method of claim 1, 2, 3, or 4, wherein R₄ isBr.
 7. The method of claim 1, 2, 3, or 4, wherein R₄ is Cl.
 8. Themethod of claim 1, 2, 3, or 4, wherein R₆ is Cl.
 9. The method in claim1, 2, 3, or 4, wherein R₆ is CH₃.
 10. The method of claim 1, 2, 3, or 4,wherein R₄ is Br and R₆ is Cl.
 11. The method of claim 1, 2, 3, or 4,wherein R₄ and R₆ are both Cl.
 12. The method of claim 1, 2, 3, or 4,wherein R₁ is CH(CH₃)₂ and R₄ is Br.
 13. The method of claim 1, 2, 3, or4, wherein R₂ is CH(CH₃ )₂ and R₄ is Br.
 14. The method of claim 1, 2,3, or 4, wherein the compound has the structure:


15. The method of claim 3, wherein the compound has the structure:


16. The method of claim 3, wherein the compound has the structure:


17. The method of claim 3, wherein the compound has the structure:


18. The method of claim 3, wherein the compound has the structure:


19. The method of claim 3, wherein the compound has the structure:


20. The method of claims 3, wherein the compound has the structure: